Glomerulosclerosis and tubulointerstitial fibrosis are attenuated with 17beta-estradiol in the aging Dahl salt sensitive rat

Christine Maric, Kathryn Sandberg, Carmen Hinojosa-Laborde, Carmen Hinojosa‐Laborde
Journal of the American Society of Nephrology : JASN · 2004 · vol. 15(6) , pp. 1546–1556 · doi:10.1097/01.asn.0000128219.65330.ea · PMID:15153565 · W2119218375
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In aging Dahl salt-sensitive rats, estrogen deficiency exacerbated glomerulosclerosis and tubulointerstitial fibrosis, while 17β-estradiol replacement attenuated these renal lesions and reversed associated molecular changes.

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This study investigated the impact of estrogen deficiency and subsequent 17β-estradiol replacement on renal pathology in aging Dahl salt-sensitive rats. The researchers compared young and aged rats, finding that ovariectomy significantly exacerbated glomerulosclerosis and tubulointerstitial fibrosis in older subjects through increased collagen deposition, elevated TGF-β expression, and reduced MMP-9 activity. Treatment with 17β-estradiol effectively attenuated these structural damages and restored functional markers, indicating a renoprotective role for the hormone. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17beta-estradiol (E(2)) replacement (OVX+E(2)) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-beta (TGF-beta), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 +/- 0.09 versus 12M, 1.43 +/- 0.17; P < 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 +/- 4.9; P < 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 +/- 0.34; CTIFI, 74.4 +/- 9.2; P < 0.01 versus Intact at 12M) and attenuated with E(2) replacement ([GSI], 1.09 +/- 0.09; CTIFI, 49.2 +/- 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 +/- 6.7; OVX, 277.4 +/- 9.6 AU; P < 0.01), increased expression of TGF-beta (Intact, 85.0 +/- 23.0; OVX, 178.0 +/- 20.5 AU; P < 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 +/- 0.8; OVX, 2.4 +/- 0.6 AUC; P < 0.01). E(2) replacement opposed these effects (laminin, 229.9 +/- 6.2 AU; TGF-beta, 101.3 +/- 25.2 AU; MMP-9, 5.2 +/- 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 +/- 0.01; OVX, 0.22 +/- 0.01; OVX+E(2), 0.28 +/- 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 +/- 2.1; OVX, 32.6 +/- 5.1; OVX+E(2), 24.3 +/- 2.4 mg/dl). The authors conclude that E(2) is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.
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Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat - Christine Maric - Kathryn Sandberg - Carmen Hinojosa-Laborde ABSTRACT. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17β-estradiol (E2) replacement (OVX+E2) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-β (TGF-β), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 ± 0.09 versus 12M, 1.43 ± 0.17; P < 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 ± 4.9; P < 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 ± 0.34; CTIFI, 74.4 ± 9.2; P < 0.01 versus Intact at 12M) and attenuated with E2 replacement ([GSI], 1.09 ± 0.09; CTIFI, 49.2 ± 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 ± 6.7; OVX, 277.4 ± 9.6 AU; P < 0.01), increased expression of TGF-β (Intact, 85.0 ± 23.0; OVX, 178.0 ± 20.5 AU; P < 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 ± 0.8; OVX, 2.4 ± 0.6 AUC; P < 0.01). E2 replacement opposed these effects (laminin, 229.9 ± 6.2 AU; TGF-β, 101.3 ± 25.2 AU; MMP-9, 5.2 ± 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 ± 0.01; OVX, 0.22 ± 0.01; OVX+E2, 0.28 ± 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 ± 2.1; OVX, 32.6 ± 5.1; OVX+E2, 24.3 ± 2.4 mg/dl). The authors conclude that E2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.

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MeSH descriptors

Estradiol Fibrosis Glomerulosclerosis, Focal Segmental Animals Blood Urea Nitrogen Blotting, Western Body Weight Collagen Type IV Collagen Type IV Creatinine Creatinine Estradiol Estradiol Estrogens Estrogens Female Fibrosis Glomerulosclerosis, Focal Segmental Immunohistochemistry Kidney

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