Sex-specific epigenetic programming in renal fibrosis and inflammation.

epigenetics, inflammation, renal fibrosis, sex differences

The growing prevalence of hypertension, heart disease, diabetes, and obesity along with an aging population is leading to a higher incidence of renal diseases in society. Chronic kidney disease (CKD) is characterized mainly by persistent inflammation, fibrosis, and gradual loss of renal function leading to renal failure. Sex is a known contributor to the differences in incidence and progression of CKD. Epigenetic programming is an essential regulator of renal physiology and is critically involved in the pathophysiology of renal injury and fibrosis. Epigenetic signaling integrates intrinsic and extrinsic signals onto the genome, and various environmental and hormonal stimuli, including sex hormones, which regulate gene expression and downstream cellular responses. The most extensively studied epigenetic alterations that play a critical role in renal damage include histone modifications and DNA methylation. Notably, these epigenetic alterations are reversible, making them candidates for potential therapeutic targets for the treatment of renal diseases. Here, we will summarize the current knowledge on sex differences in epigenetic modulation of renal fibrosis and inflammation and highlight some possible epigenetic therapeutic strategies for CKD treatment.

Epigenetics refers to the study of reversible and heritable changes (histone and DNA modifications) regulating gene expression, in the absence of any changes in the nuclear DNA sequence, that may influence gene function (for review, see Refs. 1–3). The epigenome acts as a bridge between genetics and the environment, and epigenetic modifications affect the target gene directly as a response to environmental stimuli and pathological states such as hormones, oxidative stress, inflammation, metabolic changes, and aging (for review, see Refs. 4–7). Furthermore, epigenetic responses influence cell- and tissue-specific gene expression and sex dimorphism during development and may lead to the occurrence of sex-specific diseases later in life (8). Conversely, sex-steroid hormones such as estrogen (E2) and testosterone have been shown to modulate epigenetic modifications under normal and disease conditions (9, 10). Epigenetic mechanisms are involved in X-chromosome inactivation (XCI) during early gestation in somatic cells as one of the X-chromosomes is transcriptionally silenced by the combination of histone modifications, DNA methylation, and noncoding RNA (11, 12). This ensures dosage compensation of the X-chromosome between men and women (13, 14). Chronic kidney disease has become a global health problem, with increased incidence rates and poor diagnoses. Sex contributes to differences in incidence and progression of CKD with males exhibiting a more rapid rate of decline in renal function compared to females. Some meta-analyses and most of the experimental animal models of renal injury have revealed that males of reproductive age exhibit more abnormalities in renal function and structure that lead to exacerbated progression of CKD compared to females (15). Evidently, E2 plays a renoprotective role whereas testosterone mediates a deleterious effect in terms of increasing oxidative stress, activating renin-angiotensin system, inflammation, and worsening fibrosis within the damaged kidney (16–18). The progression of kidney disease is slower in premenopausal females compared to age-matched males and increases as E2 levels decline during menopause (16). Consequently, studies have shown that older menarche age and short reproductive period increase the risk of developing CKD (19, 20), strongly suggesting that the amount of endogenous E2 exposure could be a determining factor for renal function in postmenopausal women. The common pathway of all progressive CKD is tubulointerstitial fibrosis and inflammation, which is mainly recognized by the accumulation of extracellular matrix (ECM) proteins in glomerular basement membranes and tubulointerstitium. The infiltration of proinflammatory cells into the injured kidney further promotes ECM deposition, progressively damaging renal structure and function (21, 22). The factors and mechanisms responsible for the development of renal fibrosis are still incompletely clear; however, activation of signaling pathways accompanying renal fibrosis and inflammation has proved to be regulated by a multitude of posttranscriptional and posttranslational modifications including epigenetic modifications (for review, see Refs. 23–26). In this review, we summarize the current knowledge of epigenetic mechanisms such as histone modifications (acetylation and methylation) and DNA methylation-mediated regulation of renal fibrotic and inflammatory signaling processes with an emphasis on sex differences. We have evaluated the studies by highlighting sex-specific information in the field of epigenetic modulation of renal fibrosis and we provide an account of potential therapeutic compounds showing beneficial effects in the treatment of renal fibrosis. EPIGENETICS OVERVIEW Epigenetic features include modifications of DNA (DNA methylation) or histone proteins (including acetylation, methylation, phosphorylation, and ubiquitination). The main components of chromatin are DNA and histones. Histones are proteins rich in arginine and lysine, which contain five components: H1, H2A, H2B, H3, and H4. Histone modifications are posttranslational modifications of histone protein and an indispensable part of the epigenetic layer that regulates normal cellular transcription (27). These changes occur in the exposed histone amino-terminal tails such as lysine acetylation (Kac), lysine methylation (Kme), ubiquitination, threonine and serine phosphorylation, and arginine methylation (28, 29). The alterations in histones regulate gene expression by changing the chromatin structure or accessibility of genetic loci by transcriptional machinery (27). There are specific enzymes that catalyze the reactions involved in addition of these epigenetic marks known as “writers,” and a different set of enzymes are involved in their removal also known as “erasers.” Also, these epigenetic marks are recognized by a set of functional proteins known as “readers,” which decide the consequent biological pathways, modulate chromatin accessibility, and regulate gene expression (30, 31). The balanced interaction among epigenetic regulators is well controlled in physiological conditions as it is essentially responsible for prompting chromatin state from active to inactive state or vice versa and henceforth regulates gene expression (Fig. 1A). In the past few decades, with the rapidly growing field of epigenetics, numerous studies have highlighted the link between epigenetic signaling and its role in the kidney development and progression of renal diseases as reviewed in Refs. 32–34. HISTONE ACETYLATION

to Histone Acetylation, Histone Acetyltransferases, and Histone Deacetylases Histone acetylation is a major posttranslational modification, which is a dynamic and reversible process involved in a broad array of physiological functions. There are numerous lysine (K) residues that can be acetylated in histones H3 and H4, however, the most studied lysine sites are H3K4, H3K9, H3K27, H3K36, H3K79, H4K5, H4K12, H4K20 (29, 35). The addition of an acetyl group neutralizes the positive charge of lysine and relaxes the chromatin to form an open chromatin configuration, which is required for binding of the transcription factors, henceforth associated with the transcriptional activation of the genes (30, 35, 36). Acetyl coenzyme A is the key intermediate substrate for acetylation, which influences the level of downstream histone acetylation in the nucleus (37). The addition of acetylation marks on lysine residues is catalyzed by histone acetyltransferases (HATs), sometimes referred to as “writers,” and the removal of acetyl groups is catalyzed by histone deacetylases (HDACs), sometimes referred to as “erasers” (30, 38). The acetylation marks on the histones are read by small protein modules called bromodomains (BrDs), referred to as “readers,” as reviewed in Refs. 30 and 39. Histone acetyltransferases. HATs catalyze histone acetylation and include the group of enzymes classified by the amino acid sequences and conformational homology. For a detailed list of mammalian HATs and their nomenclature (for reviews, see Refs. 40–42). The well-established HATs are cAMP response element-binding protein (CREB)-binding protein (CBP) subfamilies, including p300/CBP and p300/CBP-associated factor (PCAF), which function as transcriptional coregulators for many transcription factors and play a diverse role in development and disease progression (43–45). Histone deacetylases. HDACs catalyze the removal of acetyl groups from the ε-amino groups of lysine residues of histones and non-histones, which causes chromatin structure condensation and suppresses the activity of genes (38, 46). In mammals, 18 HDAC proteins have been identified, which are divided into the following four classes depending on their sequence similarity and cofactor requirement: class I includes nuclear enzymes, HDACs 1, 2, 3, and 8 expressed extensively in diverse tissues; class II HDACs are subdivided into two groups, IIA (HDAC4, 5, 7, 9) and IIB (HDAC6 and 10); class IV (HDAC11) are cytoplasmic enzymes, expressed in specific tissues; and class III includes silencing proteins, sirtuins (SIRT1–SIRT7) (for review, see Refs. 38 and 47). They depend on zinc for their catalytic activity, except for the class III HDACs, which require oxidized nicotinamide adenine dinucleotide (NAD+) for catalytic activity (48). The HDACs are essential for maintaining a dynamic equilibrium of protein acetylation and their tissue-specific expression exhibits different biological effects (42). The current review focuses on the role and mechanisms of class I, II, and IV HDACs in the pathogenesis of renal fibrosis and the role of SIRT1–SIRT7 in kidney disease has been recently reviewed in detail (49, 50). Sex Differences in Histone Acetylation and HAT-Mediated Renal Fibrosis and Inflammation The balance between HATs and HDACs plays a crucial role in gene expression involving various developmental processes and diseases (51). Extensive studies have reported that the level of histone acetylation and p300/CBP (the predominant HAT that catalyzes lysine acetylation leading to gene activation) plays a key role in the development and progression of renal fibrosis (25, 52, 53). We summarize the current knowledge on the role histone acetylation and HATs play in the development of renal fibrotic and inflammatory pathways and identify the conflicting observations regarding the role of histone acetylation in renal fibrosis. Role of histone acetylation and HAT-mediated renal fibrosis and inflammation in male rodent models. A progressive increase in H3 acetylation was observed in male CD-1 mice with ischemia-reperfusion (I/R)-induced renal injury together with induction of proinflammatory cytokines/chemokines [monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)] and profibrotic genes such as collagen (Col) type III and collagen deposition, which was consistent with acute kidney injury (AKI)-to-CKD transition (54). In addition, the macrophages from diabetic male C57BL/6 mice exhibited increased levels of total HAT activity associated with elevated STAT1 and MyD88 expression (55). Increased binding of acetylated H3K9 to the Stat1/Myd88 promoters was observed in the macrophages, suggesting that an epigenetic mechanism may be involved in sterile inflammation and diabetes comorbidities. Another study has demonstrated increased H3K9 and H3K23 acetylation and H3 phosphorylation at serine 10 in the kidneys of uninephrectomized diabetic male C57BLKS db/db mice characterized by increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria, and reduced glomerular filtration rate (56). However, treatment with MCP-1/CCL2 antagonist in these mice prevented the histopathological damage and reversed the histone modification changes, suggesting a role for MCP-1 in the regulation of histone epigenetics. Studies have evidenced p300/CBP as one of the predominant HATs that catalyze lysine acetylation leading to gene activation. Enhanced recruitment of P300/CBP to plasminogen activator inhibitor (Pai-1) and p21 gene promoters plays an important role in the diabetic nephropathy model of male db/db mice and diabetes-induced male C57BL/6 mice (57). In these mice models, significantly increased mRNA expression of Tgf-b1, Pai-1, and p21 in the glomeruli were observed, and TGF-β1-induced PAI-1 and p21 expression involved enhanced interaction of Smads and Sp1 with their promoter via p300/CBP-induced H3K9/14ac. PCAF also has HAT activity and regulates gene expression leading to renal fibrosis and inflammation. Increased expression levels of PCAF and H3K9ac were observed in male C57BL/6 mice after unilateral ureteral obstruction (UUO) injury, which coincided with the activation of proinflammatory nuclear factor-κB (NF-κB) signaling and reduced nuclear anti-inflammatory factor nuclear factor erythroid 2-related factor 2 (Nrf2) (58). In diabetes-induced renal injury in male db/db mice and lipopolysaccharide (LPS)-injected mice, overexpression of renal PCAF-mediated enhanced acetylation of H3K18 was observed in parallel with upregulated expression of the inflammatory genes, such as intercellular adhesion molecule (Icam)-1, vascular cell adhesion molecule (Vcam)-1, and Mcp-1 (59). Furthermore, increased H3K18ac was observed at the promoters of Icam-1, Vcam-1, and Mcp-1 in LPS-injected mice kidneys, demonstrating that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases. P300/CBP was highly expressed in the fibrotic kidneys of ANG II-induced hypertensive mice model C57BL/6 background (sex not mentioned) (60). These studies provide ample evidence that an increase in histone acetylation levels is associated with renal fibrosis and inflammation; however, in contrast, the study by Marumo et al. (61) demonstrated a decrease in renal histone acetylation levels in male C57BL/6J mice with UUO-injured kidneys (61). Similarly, our earlier studies in hypertensive male mice model with global heterozygous deletion of Npr1 [coding for natriuretic peptide receptor A (NPRA)] gene (Npr1+/−) demonstrated reduced HAT activity and attenuated levels of p300 and PCAF in the heart and kidney tissues (62, 63). The mutant Npr1+/− mice exhibited high systolic blood pressure and renal and cardiac pathology associated with increased inflammatory and fibrotic markers. We also reported decreased levels of the active histone marks such as H3K9ac and H4K12ac and increased renal expression of profibrotic markers, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) in Npr1 mutant mice kidneys (63). These conflicting observations suggest that the p300/CBP and PCAF expression levels are differentially regulated by pathology-associated intrinsic factors, and more intensive research is required to decipher their role in renal fibrosis. Role of histone acetylation and HAT-mediated renal fibrosis and inflammation in female rodent models. The implications of histone acetylation modifications in female rodent models of renal fibrosis have not been studied to the best of our knowledge. However, sex-dependent differences in H3K9/14ac expression during stress (lead exposure and prenatal stress) were demonstrated in the frontal cortex and hippocampus of male and female C57BL/6 mice (64). The authors observed reduced levels of H3K9/14 acetylation in the hippocampus of females than in males, which changed with development and was affected by sex and brain region during stress. Sex Differences in Histone Deacetylation and HDAC-Mediated Renal Fibrosis and Inflammation The expression levels of HATs and HDACs have been mapped along the nephron based on rat transcriptomic data and the collecting duct (both cortical and inner medullary), which exhibited high expression of the lysine deacetylases (HDAC1–HDAC5, HDAC10, HDAC11, and SIRT2–SIRT7) (65, 66). The HDAC activity was required for normal embryonic kidney homeostasis, and the class I HDACs played a role in the regulation of early nephron gene expression, differentiation, and survival (67). Class I HDAC activity contributed to renal protection and functional recovery as it was essential for tissue regeneration after renal injury in male C57BL/6 mice with AKI (68). Dysregulated expression of the HDACs is highly associated with different models of renal fibrosis and inflammation as observed in diabetic nephropathy, UUO, and AKI (69–72). Sex differences in HDAC expression in different brain regions have been observed (73) and suggested to be relevant to the higher occurrence of neuropsychiatric disorders and neurogenerative diseases in females. Two studies have reported sex differences in HDAC expression in renal injury as discussed below. Role of HDACs in renal fibrosis and inflammation in male rodent models. The majority of the studies, conducted in male rodents, have extensively demonstrated the involvement of enhanced HDAC activity in the causation and progression of renal fibrosis and inflammation. For example, a study in UUO-induced renal fibrosis in male C57BL/6J mice showed enhanced HDAC1 and 2 expression in the renal tubular cells associated with macrophage infiltration and fibrotic changes in tubulointerstitial injury (61). Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, suggesting that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases (74). Similarly, another group has reported increased HDAC2 activity in the kidneys of diabetic male Sprague–Dawley (SD) rats, suggesting that HDAC2 is a key regulator of diabetes- and TGF-β1-induced renal injury (75). We have also observed similar results in our study with male Npr1 gene-disrupted haplotype (Npr1+/−) mice (exhibiting hypertension, renal dysfunction, and cardiac injury), which exhibited significantly enhanced HDAC1 and HDAC2 protein levels in renal and cardiac tissues (62, 76). A recent study has demonstrated an aberrant HDAC3 induction and its inhibition of Klotho, a renal epithelium-enriched aging suppressor, associated with renal fibrogenesis in male C57BL/6 mice with UUO injury (71). A time-dependent induction of class I HDAC8 in renal tubular epithelial cells of male C57BL/6 mice with UUO injury has been observed in parallel with increased expression of fibrotic markers: α-SMA, COL type I, and fibronectin (72). Another group has demonstrated that UUO injury in male C57BL/6 mice resulted in increased expression of HDAC1 and HDAC2, decreased HDAC3, and unchanged HDAC8, associated with enhanced expression of COL type I, fibronectin, and α-SMA, implicating the important role of HDAC1 and HDAC2 in mediating renal fibrogenesis after chronic kidney injury (77). Similarly, class II HDAC members have been implicated in various forms of renal pathology; however, unlike other HDACs, class IIa HDACs have no deacetylase activity, but act as adaptors of repressor complexes (78). Increased protein levels of HDAC1, HDAC4, HDAC5, HDAC6, and HDAC10 were observed in the kidneys of UUO-injured male C57BL/6 mice, whereas that of HDAC8 was downregulated in association with renal fibrosis (79). In male C57BL/6J mice, HDAC6 was highly expressed in the kidney following UUO injury which was coincident with collagen deposition and enhanced expression of α-SMA, fibronectin, and COL type III (80). Increased expression of HDAC9 in diabetic male C57BL/6J db/db mice and in the kidney samples from patients with DKD has been observed and in vivo silencing of HDAC9 by shRNA attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis, and renal injury in the mice (81). Recently, it has been shown that in different models (UUO, high-fat diet, and ANG II-infused) of renal fibrosis in C57BL/6 mice, the levels of class IV HDAC11 increased with injury in the kidney, however, the sex of the mice was not reported in this study (82). The authors showed that HDAC11 inhibition by quisinostat suppressed the induction of profibrogenic genes such as α-Sma, Col1a1/Col1a2, Col1a3, and Tgfβ in the kidneys. Role of HDACs in renal fibrosis and inflammation in female rodent models. Sex differences have been observed in HDAC9 expression in male and female SD rats as HDAC9 mRNA and protein levels were higher in the renal cortex of female rats versus male rats whereas other HDACs did not exhibit sex differences (83). An earlier study reported sex-specific modulation of HDAC11 expression in I/R-induced renal injury in male and female BALB/c mice (84). The authors reported that male sex and male hormones accelerated I/R-induced decreases in the expression and binding of HDAC11, which resulted in an increase in PAI-1 expression and renal inflammation and dysfunction. I/R decreased the expression of HDAC9 and 11 but not HDAC1, HDAC5, and HDAC8 in male mice, suggesting that expression of HDAC9 and HDAC11 was male hormone dependent. By contrast, no significant differences in HDAC expression were observed in I/R-induced females either before or after ovariectomy. However, in males, the I/R-mediated reduction in HDAC11 was inhibited by orchiectomy and reversed by DHT supplementation. Use of HAT and HDAC inhibitors in renal fibrosis models. Recent studies have shown a beneficial effect of HAT inhibitors on renal inflammation and fibrosis in preclinical animal models and are listed in Fig. 1B and Table 1. Several pan (class I and II specific), class-specific, and isoform-specific HDAC inhibitors (HDACi) have been developed which show promising effects in treating fibrotic and inflammatory pathologies in various organs including kidneys in preclinical animal models (85–87) as shown in Fig. 1B and Table 2. As the list of HDACi is still growing with many new chemicals derived from natural products and with more emphasis on the identification of isoform-specific inhibitors, it is highly important to include both sexes in future studies to develop sex-based therapeutic drugs. It is interesting to note that HATs and HDACs have opposite effects on acetylation; however, preclinical studies have proved that both HAT and HDAC inhibitors have anti-fibrotic effects and provide protection against renal injury. Table 1. | HAT Inhibitor | Target | Renal Fibrosis Model/Sex | Effect on the Kidney and Mechanisms | Reference | |---|---|---|---|---| | C646 | p300/CBP | Type I diabetes/Male C57BL/6J mice | Inhibit inflammation and fibrosis in the diabetic kidney, reduce H3K27ac levels | 52 | | L002 | p300/CBP | ANG II-induced C57BL/6J mice (sex not mentioned) | Reduce hypertension-associated renal fibrosis, ANG II induced deposition of renal interstitial and perivascular collagen | 60 | | C66 | Curcumin analog/p300 | Type I diabetes/Male C57BL/6J mice | Prevent diabetes-induced renal fibrosis and dysfunction, decrease histone acetylation, HAT activity, and p300 expression | 53 | | Garcinol | PCAF | UUO/Male C57BL/6J mice | Inhibit progression of renal tubulointerstitial fibrosis, reduce α-SMA, TGF-β, MMP-2, MMP-9, NF-κB, TNF-α, IL-6, PCAF, and H3K9ac levels | 58 | ANG II, angiotensin II; CBP, cAMP response element-binding protein-binding protein; HAT, histone acetyltransferase; IL-6, interleukin-6; MMP, matrix metalloproteinase; PCAF, p300/CBP-associated factor; α-SMA, α-smooth muscle actin; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UUO, unilateral ureteral obstruction. Table 2. | HDAC Inhibitor | Target | Renal Fibrosis/Model Sex | Effect on kidney and mechanisms | References | |---|---|---|---|---| | Sodium valproate | Class I/II | Diabetes/Male | Inhibit renal injury and fibrosis, prevent myofibroblast activation and fibrogenesis, increase H3 acetylation | 195 | | HDACs | SD rats | ||| | VPA | Class I/II | I/R injury/Male | Prevent renal dysfunction and inflammation, reduce inflammatory cellular infiltration and TNF-α, IL-6, and MCP-1 mRNA levels | 88 | | HDACs | Wistar rats | ||| | NaBu | Class I/II | Hypertension/Male | Inhibit renal fibrosis, reduce NF-κB signaling, HDAC activity, and expression levels of proinflammatory and fibrotic markers, and improve renal function | 63, 76 | | HDACs | Npr1+/− (C57BL6) mice | ||| | Hypertension/Male | Suppress cardiac expression of hypertrophic markers and proinflammatory mediators | 62 | || | Npr1+/− (C57BL6) mice | |||| | FR276457 | Class I/II | UUO/Male | Inhibit renal interstitial fibrosis by inhibition of MCP-1 production | 89 | | HDACs | SD rats | ||| | TSA | Class I/II | UUO/Male | Inhibit renal fibroblast activation, interstitial fibrosis, α-SMA and FN levels, inhibit tubular cell apoptosis and caspase-3 activation. | 90 | | HDACs | C57BL/6J mice | ||| | UUO/Male | Alleviate renal interstitial fibrosis, reduce infiltration of M1 and M2a macrophages, facilitate M1 to M2c macrophage transition. | 91 | || | C57BL/6J mice | |||| | UUO/Male | Decrease juxtaglomerular hyperplasia and fibrosis, and associated with the plasticity of FOXP3+IL-17+ T cells | 92 | || | C57BL/6J mice | |||| | MS-275 | Class I | I/R injury/Female | Protect against renal injury and improve renal function | 93 | | HDACs | C57BL/6 mice | ||| | UUO/Male | Inhibit renal fibrosis and renal fibroblast activation, suppress TGF-β and EGFR signaling | 77 | || | C57BL/6 mice | |||| | MC1568 | Class IIa | UUO/Male | Inhibit renal fibrosis, reduce α-SMA, fibronectin, and COL1 expression | 94 | | HDACs | C57BL/6 mice | ||| | TMP195 | Class IIa | LPS-injury/Male | Reduce serum creatinine, BUN levels, and renal damage, reduce ICAM-1, MCP-1, TNF-α, and IL-1β, and HDAC4, and increase H3 acetylation | 95 | | HDACs | C57BL/6 mice | ||| | Piceatannol | HDAC 4 and 5 | UUO/Male | Inhibit renal fibrosis, suppress ECM protein like COLI, fibronectin, CTGF, and α-SMA deposition, and p38-MAPK signaling | 79 | | C57BL/6 mice | |||| | RGFP966 | HDAC 3 | UUO/Male | Inhibit renal fibrosis, derepress Klotho in fibrotic kidneys | 71 | | Tubastatin A | HDAC 6 | AKI/Male | Inhibit NF-κB phosphorylation, TNF-α, IL-6, and MCP-1 expression, and macrophage infiltration | 96 | | C57/black mice | |||| | ANG II-injury/Male ICR mice | Inhibit renal fibrosis, suppress TGF-β signaling and H4 acetylation | 97 | || | ACY-1215 | HDAC 6 | UUO/Male | Inhibit renal fibrosis and attenuate TGF-β1-mediated renal fibrogenesis | 80 | | C57BL/6J mice | |||| | PCI34051 | HDAC 8 | UUO/Male | Inhibit renal fibrogenesis, α-SMA, col1 and FN expression, and TGF-β1 signaling | 72 | | C57BL/6J mice | |||| | Quisinostat | HDAC 11 | UUO, high-fat diet | Inhibit renal fibrosis, suppress the induction of pro-fibrogenic genes such as α-SMA, Col1a1/Col1a2, Col1a3, and TGFβ in the kidneys | 82 | | ANG II/C57/BL6 mice | ANG II, angiotensin II; CTGF, connective tissue growth factor; FN, fibronectin; HDAC, histone deacetylase; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; PAI-1, plasminogen activator inhibitor-1; α-SMA, α-smooth muscle actin; TGF-β, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UUO, unilateral ureteral obstruction; VPA, valproic acid. HISTONE METHYLATION

to Histone Methylation, HMTs and Histone/Lysine Demethylases Histone methylation uses both arginine and lysine residues, which may be mono-, di-, or trimethylated. Histone methylation is more constant and stable and does not change the electrical charge of the histone proteins in contrast to acetylation. Methylation of histones provides sites for the binding of transcription regulators, which are associated with either active or repressive target gene expression, depending on the methylated residue context (31, 100). Among the most studied histone methylation marks, H3K4me1/2/3, H3K36me2/3, and H3K79me2 are related to the activation of gene transcription; however, H3K9me2/3, H3K27me3, and H4K20me3 are recognized as repressive chromatin markers (29, 101–103). Initial studies have indicated that H3 methylation on lysines 4, 27, and 79 plays an essential role in the regulation of gene expression in the developing kidney (104). Interestingly, sex dimorphic distribution of H3K4me3 (an active chromatin mark) has been documented in the brain, as out of 248 genes and loci showing sex differences in H3K4me3, females had the majority of H3K4me3 “peaks” surrounding the transcription start site of active genes as detected by ChIP assay (105). Also, the frontal cortex and hippocampus of male and female C57BL/6 mice demonstrated sex-dependent differences in H3K9/14ac and H3K9me3 expression during stress (lead exposure and prenatal stress) (64). Unlike H3K4me3, trimethylation of H3K27 is associated with repressive gene expression, in particular, with an X chromosome inactivation (XCI) (106), and genes that escape XCI are depleted in H3K27me3 mark (107). Histone methylation is regulated through the concerted action of histone methyltransferases (HMTs) that function as “writers” and histone demethylases (HDMs) or lysine demethylases (KDM) as “erasers.” Also, there are distinct effector proteins known as “readers” that recognize specific methylated lysine residues and methylation states, which are reviewed in detail elsewhere (31). Histone methyltransferases. Despite being relatively stable, histone methylation is catalyzed by HMTs, which are specific for each methylation site and their actions are precisely balanced. The methylation process of the histones is catalyzed by their specific HMTs, such as enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) (for H3K29me and H3K27me), SET7/9 (for H3K4me), G9a (for H3K9me) (86, 108), SMYD2 (one of the SET and MYND-containing lysine methyltransferases, for H3K4 and H3K36), and disruptor of telomeric silencing 1 (Dot1; for mono-, di-, and tri-methylation of H3K79) (for a review, see Ref. 103). Histone/lysine demethylases. Many lysine demethylases have been identified that function as HDMs or KDMs with varying specificities for different histone lysine residues. The first identified HDM is lysine demethylase 1 (LSD1) also known as KDM1A, which specifically removes H3K4me and H3K9me marks (109, 110). Among the many lysine demethylases, KDM3 family members contain a catalytic Jumonji C (JmjC) domain that also functions as a binding pocket for catalytically necessary cofactors and serves as HDMs. The KDM3 family has three important members, including KDM3A (JMJD1A, JHDM2A, or TSGA), KDM3B (JMJD1B, JHDM2B, or 5qNCA), and JMJD1C (JHDM2C or TRIP8) (111). KDM3A/B-mediated demethylation of H3K9 enhances transcriptional activity of their target genes as highly methylated H3K9 is a transcriptional repressor mark and forms heterochromatin (112). KDM6A/B-mediated demethylation of H3K27 constitutes an important epigenetic mechanism of gene activation, and both KDM6A/B containing JmjC domain have been implicated in a wide myriad of diseases (113). Sex Differences in Histone Methylation and HMT-Mediated Renal Fibrosis and Inflammation Numerous studies have demonstrated that aberrant expression or activity of HMTs are linked with the development and prognostic state of various kidney diseases in human and animal models such as AKI, CKD, diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma and can be therapeutic targets for kidney diseases (5, 103, 114). Role of histone methylation and HMT-mediated renal fibrosis and inflammation in male rodent models. The pattern of histone methylation has not been studied in renal injury, though there is information on specific methylation marks from studies conducted in male rodents. For example, studies in male C57BL/6 mice with UUO injury demonstrated enhanced global kidney H3K9me3 (115) and H3K27me3 (116). We have also observed in our study in male Npr1+/− mice with renal injury showing increased H3K27me3, H3K9me2, and H3K9me3 levels in histones extracted from the whole kidney, associated with renal fibrosis (63). Histone methylation was associated with progressive glomerulosclerosis in diabetic male C57BLKS db/db or nephrectomized male C57BLKS mice, which was reverted with anti-CCL2 antibody treatment, suggesting a role for CCL2 or inflammation in epigenetic regulation (56). Furthermore, there are studies reporting altered histone methylation for specific genes, e.g., after the onset of I/R injury in male CD-1 mice, increased H3K4me3 mark was observed, which was closely associated with enhanced expression of inflammation-related gene (TNF-α), fibrosis-related genes (TGF-β1, COL type III), ultimately leading to a gradual transition from acute to chronic renal injury (54, 117). On the contrary, our study in male Npr1+/− mice with renal injury showed attenuated levels of H3K4me3 (63), suggesting its role in decreased expression of genes involved in renal protection in these mice. It is interesting to note that H3K9 can be both acetylated and methylated (118), and H3K9ac (25) and H3K9me3 (119) have been directly implicated in fibrogenesis. However, in male C57BL/6 mice with UUO induced-fibrotic kidney, H3K9me3 increased after injury, and it was expressed in various cell types including proximal tubules and myofibroblasts (115). The authors also reported that in primary rat renal fibroblasts isolated from fibrotic rats, H3K9ac was co-localized with phosphorylated-Ser2 RNA polymerase II (pRNAPol II), whereas H3K9me3 was not, which is consistent with permissive and repressive effects on gene expression, respectively. An increase in expression of renal EZH2 (for H3K29me and H3K27me), was observed accompanied by an increased level of H3K27me3 in the kidneys of male C57BL/6 mice injured with UUO (116). The HMT G9a catalyzes repressive chromatin marker, monomethylation and dimethylation at H3K9 (me1 and me2) (120, 121). Expression of G9a and its role in a murine model of UUO-injury in male C57BL/6 mice was studied by Irifuku et al. (122), and it was reported that G9a expression levels were upregulated in the injured mice kidneys and inhibition of H3K9me1 suppressed TGF-β1-induced α-SMA and fibronectin expression in renal fibroblast cells (122). The HMT SUV39H1 catalyzes the trimethylation of H3 (H3K9me3), and it is a well-known transcriptional repressor of inflammatory genes. It has been reported that hyperglycemia decreased the expression of SUV39H1 and increased the protein levels of HMT SET7/9 in diabetes-induced renal fibrosis in male Wistar rats (123). The authors observed globally increased levels of histone marks associated with active genes (H3K4me2 and H3K79me2) and decreased levels of repressive marks (H3K9me2) in their study. The HMT SET7/9 methylates histone H3K4, and several studies have indicated that SET7/9–mediated H3K4 methylation is related to renal disease and plays a role in diabetes- and UUO-induced renal fibrosis and inflammation. Increased recruitment of SET7/9 in macrophages in parallel with increased inflammatory gene expression have been observed in male diabetic mice and targeted silencing of SET7/9 reduced TNF-α-induced recruitment of NF-κB p65 to the inflammatory gene promoters (124). Another study in male db/db mice has demonstrated that SET7/9-mediated H3K4me1 is involved in the expression of MCP-1 in the kidneys (125). TGF-β1-induced upregulation of ECM-associated genes was accompanied by increased expression of H3K4me1/2/3 and SET7/9 in male rat mesangial cells (119), and a TGF-β1-mediated increase in the expression of SET7/9 was also observed in peritoneal fibrosis in male C57BL/6 mice (126). Evidence for the involvement of SET7/9 in renal fibrosis comes from a study by Sasaki et al. (127), which showed that administration of Sinefungin suppressed the expression of mesenchymal markers and ECM proteins and inhibited H3K4 mono-methylation (H3K4me1) in the kidneys of male C57BL/6J UUO-injured mice (127). Role of histone methylation and HMT-mediated renal fibrosis and inflammation in female rodent models. To our knowledge, there is no information on sex differences in specific histone methylation marks or HMTs in renal context due to a lack of studies in female rodents. A recent study has reported sex differences in liver metabolism and liver fibrosis to be controlled by EZH1 and EZH2 methyltransferases (128). The authors detected that the H3K27 trimethylation mark was a significant sex-biased repressive mark localized on many female-specific expressed genes of male mouse livers but not on male-biased genes of female mouse livers. However, no studies have been conducted in female mice in context with renal fibrosis. Role of histone methylation and HMT-mediated renal fibrosis and inflammation in humans (combined sex analysis). There are some case-control studies in humans that have documented changes in histone methylation marks in kidney tissues of male and female patients with renal disease; however, the results are not reported separately for both sexes. A dramatic increase in the expression of renal EZH2 was observed accompanied by an increased level of H3K27me3 in kidney biopsy samples of patients with focal segmental glomerulosclerosis and IgA nephropathy and in the kidneys of male C57BL/6 mice injured with UUO (116). In another study, it was found that G9a expression levels were upregulated in the human kidney biopsy specimens obtained from male and female patients with IgA nephropathy (122). Recent studies have shown contrary observations regarding SUV39H1 expression as Wang et al. (129) reported overexpression of SUV39H1 and H3K9me3 in renal tubules of male and female patients with diabetic nephropathy coinciding with proinflammatory mediators, IL-6 and MCP-1 expression (129); however, in diabetes-induced renal fibrosis in Wistar rats, hyperglycemia decreased expression of SUV39H1 (123). Also, it was observed that SET9 regulated TGF-β1-induced activation of renal fibroblasts in human diseased cells by promoting Smad-3 activation (130). Interestingly, expression of SET7/9 positively correlated with the degree of interstitial fibrosis in human kidneys of male and female patients with IgA and membranous nephropathy (127). Sex Differences in HDM-Mediated Renal Fibrosis and Inflammation Dynamic regulation of lysine methylation and demethylation can play an important role in various diseases including renal diseases (119, 131). All the studies, performed in male rodents, have shown the involvement of specific HDMs in renal fibrosis. Studies have reported that both KDM3A and KDM3B can interact with androgen receptor and demethylate H3K9me1/2 (112, 132, 133). On the other hand, female Kdm3b knockout (Kdm3bKO) mice exhibited restricted postnatal growth, female infertility, and increased levels of H3K9me1, H3K9me2, and H3K9me3 in the ovary and uterus (134). The authors also observed that Kdm3b ablation in female mice decreased the expression of insulin-like growth factor binding protein (IGFBP-3) in the kidney and in the blood leading to degradation of IGF-1. Another study from the same authors showed that knockout of Kdm3b in male mice decreased spermatogenesis (133). Role of histone demethylation and HDM-mediated renal fibrosis and inflammation in male rodent models. A recent study in male C57BL/6 mice with UUO injury showed enhanced expression of lysine demethylase 1 (LSD1) in parallel with renal fibrosis associated with epithelial-mesenchymal transition (EMT) and fibrotic markers (α-SMA and fibronectin), which was reversed with inhibition of LSD1 with its specific inhibitor ORY1001 (135). In another study of UUO-induced renal injury in male SD rats with severe histopathological damage, collagen deposition, reduced E-cadherin, and increased α-SMA levels had enhanced levels of LSD1, and in vivo inhibition of LSD1 with its specific inhibitor ORY1001 ablated renal injury by reversing the progression of TGF-β1-mediated fibrosis (136). Overexpression of LSD1 was observed in diabetic male SD rats with renal fibrosis in parallel with enhanced TGF-β signaling; however, knockdown of LSD1 decreased the expression of serum biochemical markers, including urine output (24 h), urinary protein (24 h), serum creatinine, blood urea nitrogen, and urinary albumin creatinine ratio and reduced renal fibrosis (137). Jumonji domain containing-3 (JMJD3), a specific HDM for regulation of H3K27 trimethylation, is associated with the pathogenesis of many diseases; however, a recent study has demonstrated anti-fibrotic effect and increased expression levels of JMJD3 and H3K27me3 in the male C57BL/6 mice kidneys subjected to surgical nephrectomy and UUO (138). The authors also reported that inhibition of JMJD3 either pharmacologically (with GSKJ4) or by genetic deletion increased renal dysfunction, ECM protein deposition, and activated renal interstitial fibroblasts in the injured kidney. This coincided with the decreased expression of Smad7 and enhanced expression of H3K27me3, Tgfβ1, Smad3, Notch1, Notch3, and Jagged1, suggesting that JMJD3 confers antifibrotic effects by limiting activation of multiple profibrotic signaling pathways. Role of histone demethylation and HDM-mediated renal fibrosis and inflammation in female rodent models. To the best of our knowledge, the impact of histone demethylation in renal fibrosis has not been studied in female rodent models. Nevertheless, a recent study has shown that KDM5B and KDM5C demethylases (H3K4-specific demethylase enzymes) contribute to differences in the alcohol response in the liver molecular pathways between male and female C57BL/6J mice (139). The authors reported that the KDM5B and KDM5C-mediated downregulation of the aryl hydrocarbon receptor pathway was a female‐specific mechanism of fibrosis development in alcohol‐fed mice. Use of HMT and HDM/KDM inhibitors in renal fibrosis models. Increasing evidence has documented increased expression of some HMTs such as EZH2, G9a, SUV39H1, and SET7/9 and KDMs in renal fibrosis and inflammation. Pharmacological targeting of the HMTs/KDMs has shown encouraging results in the attenuation of renal fibrosis in animal models as summarized in Table 3 and Fig. 1B. Moreover, the majority of these current preclinical studies related to pharmacological inhibition or genetic ablation are conducted in male animal models of renal disease, henceforth, more research is required to evaluate the efficacy in females as some of the HMTs/KDMs and methylation marks show sex dimorphism in brain, however, not explored in the kidney. Table 3. | Inhibitor | Target | Renal Fibrosis Model/Sex | Effect on Kidney and Mechanisms | References | |---|---|---|---|---| | HMT Inhibitor | |||| | 3-DZNeP | EZH2 | UUO/Male | Inhibit renal fibrosis | 98 | | C57BL/6 mice | |||| | I/R injury/Male | Inhibit renal tubulointerstitial fibrosis, and reduce H3K27me3 levels | 99 | || | C57BL/6J mice | |||| | I/R/Male | Inhibit renal dysfunction and tubular injury, suppress the production of TNF-α, MCP-1, IL-6, and IL-18, and impaired the recruitment of CD3+ T cells and F4/80+ cells in I/R kidneys | 196 | || | C57BL/6J mice | |||| | BIX01294 | G9a | UUO/Male | Inhibit renal fibrosis, increase Klotho expression, and decrease H3K9me1 levels | 122 | | C57BL/6 mice | |||| | Sinefungin | SET7/9 | TGF-β1/Male | Inhibit peritoneal fibrosis, suppress expression of mesenchymal cells and collagen deposition, and decrease H3K4me1 levels | 126 | | C57BL/6 mice | |||| | HDM/KDM Inhibitor | |||| | ORY1001 | LSD1 | UUO/Male | Inhibit renal fibrosis-associated with EMT and fibrotic markers (α-SMA and fibronectin) | 135 | | C57BL/6 mice | |||| | GSKJ4 | JMJD3 | UUO/Male | Increase renal dysfunction, deposition of ECM proteins, and activation of renal interstitial fibroblast | 138 | | C57BL/6 mice | ANG II, angiotensin II; HDM, histone demethylase; HMT, histone methyltransferase; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; IL, interleukin; I/R, ischemia/reperfusion; JMJD3, Jumonji domain containing 3; KDM, lysine demethylase; LSD1, lysine demethylase 1; MCP-1, monocyte chemoattractant protein-1; α-SMA, α-smooth muscle actin; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UUO, unilateral ureteral obstruction. DNA METHYLATION

to DNA Methylation and DNMTs DNA methylation (DNAme) characteristically results in a chromatin configuration that represses gene transcription. It is catalyzed by DNA methyltransferases (DNMTs), also known as “writers,” which mediate the transfer of a methyl group bound to S-adenyl methionine to the fifth carbon of cytosine, forming 5mC (1). DNA methylation is “read” by a family of methyl-CpG-binding domain (MBD) proteins that includes methyl-CpG binding protein 2 (MeCP2) and MBD1–MBD4 (140). In general, methylation of the promoter region is associated with attenuated gene expression, which is a common mechanism to physiologically silence genes to prevent chromosomal instability caused by the transcription of repetitive sequences (141, 142). On the other hand, methylation of the gene body is commonly associated with active gene transcription (143). In mammals, methylation is restricted to CpG dinucleotides and methylation of CpG promoters may suppress gene expression by ensuing either of the two mechanisms: either by direct inhibition of the recruitment of transcription factors to the promoter or indirectly by recruitment of DNAme readers to form a repressor complex on the promoter (142). Most epigenetic imprints, particularly DNA methylation (DNAme) are laid down during the in utero period, for example, hypertension and nephron endowment are significantly influenced by the in utero environment (including epigenetic programming) coinciding with the critical period of fetal development and may provide a mechanism for maternal-fetal transmission of chronic disease (for reviews, see Refs. 144–147). DNA methylation showed sex dimorphism in SD rats with female brains having higher levels of DNAme corresponding with more methylated CpG sites than males (148). Sex differences have been observed in global DNAme levels in humans, as higher global 5-methylcytosine (5mC) content was observed in blood DNA of healthy males compared with females, and global hypomethylation was observed in male patients with schizophrenia (149) and decreased with aging (150, 151). DNA methylation regulates gene expression by recruiting MeCP2 and nuclear receptor corepressor (nCOR) proteins to form a large repressor complex. Sex dimorphic expression of DNMT, MeCP2, and nCOR was found in the brain amygdala, with female rats having higher levels that male rats (152, 153). DNA Methyltransferases DNA methylation is catalyzed by DNMTs and the family consists of DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3-like (DNMT3L) (143, 154). Among these, DNMT1, DNMT3a, and DNMT3b are the principal mediators of DNAme in mammals (87). DNMT1 functions during DNA replication to copy the DNAme pattern from the parental DNA strand onto the newly synthesized daughter strand to maintain methylation marks also known as “maintenance DNMT,” whereas DNMT3a and DNMT3b establish a new methylation pattern to unmodified DNA and are known as “de novo DNMT” (1, 143). Sex Differences in DNA Methylation and DNMT-Mediated Renal Fibrosis and Inflammation Alterations in DNAme play a significant role in cardiovascular diseases, CKD, diabetes, inflammation, schizophrenia, and aging (149, 155–157). Several case-control studies in humans have documented changes in DNAme patterns in CKD patients utilizing leucocyte, urine, and/or kidney tissue DNA methylation (155, 158–161). However, most of the studies discussed in Role of DNA methylation and DNMT-mediated renal fibrosis and inflammation in humans (combined sex analysis) have reported pooled results from male and female subjects. Role of DNA methylation and DNMT-mediated renal fibrosis and inflammation in male rodent models. An earlier study has shown that Dnmt1 and Dnmt3a were highly enriched in the nephrogenic zone of the developing kidneys in the male pups of Wistar–Kyoto rats and the pups exhibited decreased methylation levels under in vitro high-glucose conditions as well as in intrauterine growth restriction model of placental insufficiency (162). The authors also reported that conditional depletion of Dnmt1 but not Dnmt3a and Dnmt3b in the murine nephron progenitor population led to hypoplastic kidneys, with reduced nephrogenesis, and transcriptional changes in the nephrogenic niche. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnmt3b) mimicked nutritional models of kidney growth restriction and resulted in a substantial reduction of nephron number as well as renal hypoplasia at birth (162). In male C57BL/6 mice with UUO-induced renal injury, TGFβ enhanced DNMT1 and DNMT3a expression that suppressed Klotho levels (a kidney-enriched antiaging and fibrosis-suppressing protein) by hypermethylation, eliminated Klotho’s antifibrotic activities, and potentiated renal fibrogenesis (163). Studies have suggested that MeCP2 regulates the gene expression of macrophages (164). A recent study of renal fibrosis in male C57BL/6 mice has demonstrated that MBD2 promoted the differentiation of resting M0 macrophages to polarized M2 macrophages but also induced them to polarized M1 macrophages and the transition of M2 to M1 macrophages, contributing to UUO- and I/R-induced renal fibrosis (165). In addition, the authors reported that MBD2-LysMCre mice exhibited substantially reduced UUO-induced infiltration of M1 and M2 macrophages and upregulated TNF-α and IL-1β (an M1 marker) as well as TGF-β1 and Arg1 (an M2 marker) via downregulation of G0S2. Role of DNA methylation and DNMT-mediated renal fibrosis and inflammation in humans (combined sex analysis). Studies have provided clinical evidence of the association between DNAme variations and fibrosis in human CKD by using appropriate kidney samples, representing an important step in the CKD epigenome research (160, 166, 167). For example, in a genome-wide study of DNA methylation pattern associated with rapid loss of kidney function in male and female participants of chronic renal insufficiency (CRIC) using the Infinium HumanMethylation 450 K BeadChip found that CpG islands of (NPHP4, IQSEC1, and TCF3) genes were hypermethylated in subjects with stable kidney function, which are known to promote the epithelial to mesenchymal transition and renal fibrosis (166). Moreover, genes involved in oxidative stress and inflammatory pathways in CKD such as NOS3, NFKBIL2, CLU, NFKBIB, TGFβ3, and TGFβI were also found to be differentially methylated. In another study in patients with CKD, 23 differentially methylated genes were identified with a strong biological and functional relevance to CKD pathogenesis in leukocyte DNA isolated from male and female cases (patients with CKD) and control (individuals with no renal disease) (155). A study examining cytosine methylation changes in profibrotic genes in the human renal samples collected from healthy living transplant and surgical nephrectomies showed that 40% of the genes, which are near the differentially methylated (DMR) regions were differentially expressed in the CKD samples (161). Their result from gene ontology and network analyses emphasized differences in cell adhesion (collagens and laminins) and development-related pathways and significant enrichment for differential expression and methylation in the TGFβ pathway, especially in TGFBR3, SMAD3, SMAD6, known to be critical in renal fibrosis and CKD development (161). A recent epigenome-wide DNA methylation profiling study of male and female patients with CKD showed 319 large genomic regions and 4.5 k probes that were differentially methylated in the arteries of patients with CKD (167). This study showed that differentially methylated genes were associated with CKD, like regulators of cell adhesion proteins, ECM, signaling pathways involved in fibrosis, such as collagen, fibronectin, and other structural components, the TGFβ signaling pathway, and SMAD proteins. The authors found that signaling molecules of the TGFβ (TGFβ1, TGFβ1l1, and SMAD3) and FGF (FGF1, FGF6, and FGFBP2) pathways were hypomethylated in CKD. Role of DNA methylation and DNMT-mediated renal fibrosis and inflammation in humans (sex-specific analysis). Although, studies exploring the role of DNAme in various forms of renal diseases have been conducted in humans including both sexes, however, the results have not been segregated according to sex and very few studies have analyzed the results with sex as one of the variables. For example, sex differences were reported in DNA methylation in DNA extracted from saliva of male and female diabetes patients with no signs of diabetic nephropathy (for >10 yr) and diabetic patients with end-stage renal disease treated by hemodialysis (160). The results from the unsupervised hierarchical cluster analysis for all CpGs revealed that both the groups did not cluster separately; however, there was clustering of most females separately from males, suggesting a robust detection of interindividual methylation differences between sexes, most likely at genes on the X chromosome. In another study of DNA hypermethylation and inflammatory markers in Japanese patients undergoing dialysis, global DNA hypermethylation was associated with ferritin and procalcitonin, a marker of inflammation due to bacterial infections, however, no significant differences were noted in age, sex, diabetes, anemia or serum albumin levels (168). In contrast, Bell et al. (169) demonstrated that significant components of DNAme variation correlated with patient age, time to onset of diabetic nephropathy, and sex. The authors studied DNAme profiling in bisulfite-converted DNA from male and female cases of type 1 diabetes mellitus and controls using Illumina Infinium HumanMethylation27 BeadChip and identified 19 prospective CpG sites associated with the risk of diabetic nephropathy (169). Use of DNMT inhibitors in renal fibrosis models. Since methylation plays a significant role in the progression of renal fibrosis, it supports the role of demethylating agents in preventing or slowing the development of CKD. Currently, demethylase inhibitors, 5-azacytidine (5-aza) and 5-aza-2′-deoxycytidine (decitabine) are in clinical use, which are approved for the treatment of specific forms of myelodysplastic syndrome and acute myeloid leukemia (170). A potential role of 5-Aza in the inhibition of progressive renal fibrosis and renal failure has been observed in folic acid-induced renal fibrosis in CD1 mice (171). This group demonstrated that Rasal1 was hypermethylated in the injured mice and treatment with 5-aza significantly reduced the accumulation of activated fibroblasts, as well as the expression of αSMA and COL type I. The study also showed that hypermethylation of Rasal1 was mediated by the methyltransferase DNMT1 during renal fibrogenesis and renal fibrosis was ameliorated in Dnmt1+/− heterozygous mice kidney (171). In a diabetic male C57BL/KsJ db/db mice, enhanced expression of DNMT1, Sp1, and NFκB-p65 was observed, which was accompanied by alleviation of glomerular hypertrophy, mesangial matrix expansion, and podocyte injury (172). The increased expression of DNMT1 was attenuated after treatment with 5-aza or decitabine or Dnmt1 knockdown accompanied with reversal of albuminuria. Hydralazine is an antihypertensive agent that has been in clinical use since the 1950s (173) and it is now being investigated for its potential effect in experimental mouse models of kidney fibrosis as it exhibits demethylation properties (174, 175). In UUO-induced renal fibrosis in C57BL/6 mice, it was observed that fibrosis was associated with increased Rasal1 CpG island promoter methylation, whereas treatment with either 5′-aza or hydralazine significantly reduced fibrosis and Rasal1 methylation (174). In their second model of I/R injury in C57BL/6 mice, treatment with hydralazine induced CpG promoter demethylation and subsequently attenuated renal fibrosis and preserved renal function (175). However, there are conflicting reports about the efficacy of DNA methylase inhibitors, e.g., treatment with decitabine transiently increased renal injury and showed a moderate inhibitory effect on DNMT expression and global DNA-methylation upon immediate treatment, none of the treatment regimens (immediate and short-term) succeeded in preventing, attenuating, or diminishing fibrosis in the long run in male C57BL/6 mice with unilateral I/R injury (176). Unfortunately, 5-aza and decitabine have demonstrated significant adverse effects as they have broad demethylating activity and considerable cytotoxicity when incorporated into the DNA (170, 174). Consequently, these drugs are of limited use in the setting of CKD prevention. Interestingly, a recent study has demonstrated that Zebularine, a DNMT inhibitor, significantly attenuated renal tubulointerstitial fibrosis and inflammation in male C57BL/6 mice with UUO-induced renal injury (177). Zebularine downregulated mRNA expression levels of matrix metalloproteinase-2 and -9 (Mmp-2 and Mmp-9, respectively) fibronectin and suppressed the activation of proinflammatory NF-κB and the proinflammatory cytokines, including Tnf-α, Il-1β, and Il-6 in the obstructed kidneys. DNMT inhibitors used currently in preclinical renal injury models are listed in Fig. 1B. In summary, ample studies in human CKD have demonstrated the relationship between DNA methylation and fibrosis. Few studies in human patients with CKD and DNA methylation have included both sexes, which is encouraging; however, the results are not stratified by sex, despite the epidemiological evidence of sex-specific differences in outcomes of all stages of CKD. Sex differences have been observed in methylation levels and expression of various DNMTs in the brain (178, 179). Therefore, a better understanding of the multifaceted relationship between DNA methylation and sex differences in disease development and progression is needed to improve the ability to identify individuals at risk of CKD and enable appropriate disease management. EPIGENETIC MODULATION OF SEX DIMORPHISM/SEX HORMONES Epigenetic mechanisms are well documented in the sex differences in the regulation of gene expression in the brain as evidenced in rodents during early development, there was transient hypoacetylation in the hippocampus of females compared with males (73, 178–180). A positive relationship among histone acetylation, decreased HDAC2 levels, and E2-induced memory enhancement has been observed in females (181). Moreover, HDACs can modulate and respond to sex-steroid hormones such as E2, and histone deacetylation during brain development is essential for permanent masculinization of behavior (181, 182). In another study, acetylation of human SRY (a Y chromosome-encoded DNA-binding protein, required for testis organogenesis in mammals) gene with p300 participated in the nuclear localization of SRY and deacetylation by HDAC3 induced a cytoplasmic delocalization of SRY in both human and mouse gonadal development, which maybe an important mechanism for regulating SRY activity during mammalian sex determination (183). In female mammals, lack of H4 acetylation distinguishes the inactive X chromosome, which is a cytogenetic marker for gene expression (184). Females and males display differences in the progression of renal pathology; however, very little information is available on the sex differences underlying the epigenetics mechanisms-mediated regulation of renal physiology and pathophysiology. Several studies have documented the epigenetic control of E2 and its receptor signaling in development and disease state such as cancer, endometriosis, and aging (80, 185–187). For example, histone H3K9 demethylase Kdm3b that demethylates monomethylated and dimethylated K9 of H3 (H3K9me1 and H3K9me2) played an essential role in the maintenance of the circulating IGF-1, postnatal somatic growth, circulating E2, and female reproductive function (134). The authors showed that female Kdm3bKO mice exhibited severely impaired reproductive function and increased levels of H3K9me1, H3K9me2, and H3K9me3 in the ovary and uterus. DNA methylation of estrogen receptor (ER)-α and -β gene promoters in human aging and atherosclerosis in the cardiovascular system have been observed (188, 189), which in turn can partially explain the failure of E2 therapy to display cardioprotective effects in females. Another epigenetic mark, a class III HDAC, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis as discussed in a recent review article (190) and a link between SIRT1 and E2 has been suggested. In addition, SIRT1 regulated ERα expression and inhibition of SIRT1 suppressed ERα expression (191). Moreover, a pan HDACi, valproic acid (VPA), used as an antiepileptic drug, and its derivatives have been shown to interact with E2 signaling with structural specificity, whereas the (anti-) androgenic effects of these compounds were not structurally correlated (192). Treatment with genistein, a phytoestrogen isoflavone enriched in dietary soy products, in male C57BL/6 mice with UUO-induced fibrotic kidneys, exhibited reversal of renal fibrosis by recovering epigenetic loss of Klotho gene (193). The underlying mechanism was genistein-mediated inhibition of HDAC3 on Klotho promoter and promoter DNA hypermethylation by suppressing elevated DNMT1 and DNMT3a (193), suggesting a renal protective effect of natural estrogenic flavonoid with epigenetic modulation. Also, the demethylating agent decitabine, which is used in anticancer therapy, was able to restore the expression of both ER genes and other hypermethylated genes (194). Indeed, a combination of epigenetic and hormone replacement therapy may be beneficial in the treatment of CKD. A better understanding of sex-specific renal epigenetics will provide further insight into the development of novel therapeutic approaches for the treatment of renal disorders characterized by sex differences.

Our overview clearly shows that several studies in the past few decades have confirmed that epigenetic modifications (such as histone modifications and DNA methylation) play an important role in the progression of renal injury. There is a noticeable gap in our knowledge of how sex impacts epigenetic modifications in renal function and injury, as most studies have been performed on male rodents. Furthermore, it is well known that aging increases the progression of kidney diseases in females, with the onset of menopause, highlighting the need to identify the epigenetic regulators and modifications involved in sex hormone-driven pathways and how the loss of hormones impacts epigenetic modifications and disease progression. A small number of studies have employed genome-wide approaches to assess sex differences in the renal epigenomic landscape. Even though women have differing underlying physiology, addressing sex differences is an important and overlooked area leading to a lack of sex-specific clinical practice guidelines or therapeutic targets. Moreover, there is an increase in awareness of the differential effects of drugs on males and females in the treatment of disease. There is also a compelling need to identify easily accessible epigenetic biomarkers in body fluids (in a minimally invasive manner), whether by using whole blood or in silico techniques, which will help to identify patients at a higher risk of developing CKD. Thus, the development of epigenetic biomarkers could help us assess how future therapies delay the progression of CKD following renal injury. In summary, a comparative analysis and integration of multidimensional datasets is needed to evaluate biological networks involved in sex differences in kidney function and disease onset. The availability of sophisticated technologies, transposase-accessible chromatin sequencing (ATAC-seq), RNA-seq, and single-cell chromatin state analysis will facilitate our understanding of sex-specific epigenetic signaling in the kidney. This in turn will allow us to understand how kidney function and the epigenetic landscape are impacted by aging, specifically in women where menopause leads to an acceleration of kidney disease and hypertension. GRANTS This work was supported by National Institutes of Health/National Institute on Aging Grant R03AG075396 (to P.K.) and NIH Grant R01HL131834 (to H.L.B.). DISCLOSURES Heddwen L. Brooks is the Editor-in-Chief of the American Journal of Physiology-Renal Physiology and was not involved and did not have access to information regarding the peer-review process or final disposition of this article. An alternate editor oversaw the peer-review and decision-making process for this article. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. AUTHOR CONTRIBUTIONS P.K. prepared figures; P.K. drafted manuscript; H.L.B. edited and revised manuscript; P.K. and H.L.B. approved final version of manuscript. ACKNOWLEDGMENTS The author(s) acknowledge the training received by P.K. in Dr. Kailash N. Pandey’s research laboratory.

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