Estrogens do not protect, but androgens exacerbate, collagen accumulation in the female mouse kidney after ureteric obstruction

Tim D. Hewitson, Wah Chin Boon, Evan R. Simpson, Edward R. Smith, Chrishan S. Samuel
In: Life Sciences · 2016 · vol. 158 , pp. 130–136 · doi:10.1016/j.lfs.2016.06.022 · PMID:27373424 · W2463336269
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In female mice lacking estrogens, androgens exacerbated renal fibrosis following ureteric obstruction by reducing matrix metalloproteinase-2 activity, indicating that androgens rather than estrogens regulate disease-related scarring.

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Abstract

AimsControversy surrounds the gender basis of progression in chronic kidney disease. Unfortunately, most experimental studies addressing this question do not distinguish between direct effects of estrogen and indirect activation of estrogen receptors through conversion of testosterone to 17β-estradiol by aromatase. We examined the pathogenesis of renal fibrosis in female aromatase knockout (ArKO) mice, which lack circulating and stored estrogens, while having normal levels of testosterone.Main methodsArKO mice and their wild-type (ArWT) counterparts were subjected to unilateral ureteric obstruction (UUO), with kidney tissue collected at day(D) 0, 3 and 9 post-UUO. Effects of 5α-dihydrotestosterone (DHT) administration on each genotype were also studied. Tissue was assessed biochemically and histochemically for fibrosis. Western blot analysis was used to measure α-smooth muscle actin (α-SMA) expression and TGF-β1 signalling. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography.Key findingsUUO increased collagen content over time (p<0.05 (D3) and p<0.01 (D9) vs day 0), with no difference between genotypes in qualitative (collagen IV staining) and quantitative (hydroxyproline concentration) analyses. Systemic administration of non-aromatizable DHT increased collagen content after 3days of UUO in both genotypes. This was not paralleled by any change in α-SMA (myofibroblast burden) or TGF-β1 signalling but was commensurate with DHT reducing MMP2 activity in both genotypes (p<0.05 vs genotype controls).SignificancePhysiological concentrations of estrogens do not protect the injured kidney from fibrosis progression. Androgens rather than estrogens are the relevant factor involved in regulating disease-related renal scarring in this model.

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SciLite annotations

chemicals 12
estrone androgen estrogen testosterone estradiol estrone testosterone delta(1)-dihydrotestosterone hydroxyproline estrone androgen estrone
organisms 3
transgenic mice mus sp. mus sp.

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