Beneficial Effects of Estrogens on Indices of Renal Damage in Uninephrectomized SHRsp Rats

Abstract

Abstract. Renal diseases tend to be less severe among premenopausal female patients, compared with male patients. Experimental data on the effects of estrogens on renal damage are controversial, and potential underlying mechanisms have not been fully clarified. Three-month-old, female, uninephrectomized (UNX), sham-operated or ovariectomized (OVX) SHRsp rats were left untreated or received either 17␤-estradiol 3-benzoate (25 g/d) or estriol (0.02 mg/d) daily. After 3 mo, indices of renal damage (glomerulosclerosis index and tubulointerstitial damage index) and glomerular geometric parameters were investigated. The expression of desmin, TGF-␤, endothelin-1, collagen IV, endothelial nitric oxide synthase, and estrogen receptors ␣ and ␤ in the glomeruli and tubulointerstitium was immunohistochemically evaluated. Estradiol and estriol did not significantly affect kidney weights or BP. Estradiol and estriol caused significant reductions in albuminuria (vehicle-treated UNX/OVX animals, 25.4 Ϯ 8.52 mg/24 h; estradiol-treated UNX/OVX animals, 15.37 Ϯ 6.12 mg/24 h; estriol-treated UNX/OVX animals, 6.54 Ϯ 2.24 mg/24 h). The glomerulosclerosis index was significantly lower in estriol-and estradiol-treated animals (estradiol-treated UNX/OVX animals, 0.69 Ϯ 0.16; estriol-treated UNX/OVX animals, 0.21 Ϯ 0.12; P Ͻ 0.05), compared with vehicle-treated animals (1.46 Ϯ 0.09); the tubulointerstitial damage index exhibited a similar pattern. The mean glomerular volume was significantly less in estrogen-treated animals. UNX/OVX animals demonstrated significantly greater expression of TGF-␤ and endothelin-1 in immunohistochemical, in situ hybridization, and reverse transcription-PCR assays. This increase was abrogated by estriol but not estradiol. Similarly, significantly higher glomerular and tubulointerstitial expression of proliferating cell nuclear antigen and collagen IV was observed in UNX/OVX animals, and expression was decreased by estriol but not estradiol. It was concluded that, in the UNX model of spontaneous renal damage, glomerular lesions and glomerular hypertrophy were reduced by estriol but less consistently by estradiol. In parallel, loss of podocytes, evidence of podocyte injury (i.e., desmin expression), and expression of mediator systems of glomerular damage were decreased, pointing to a major renoprotective action of estriol.Several studies have demonstrated that the severity and rate of progression of renal diseases tend to be greater among men, compared with women (1). This is true for several types of renal diseases, such as membranous nephropathy (2), IgA nephropathy (3), and polycystic kidney disease (4). The data from experimental studies are controversial, and very few molecular data are available. Estrogens or estrogen metabolites ameliorate renal damage in some (5) but not all (6,7) models of renal damage. The beneficial effect of estrogen was also noted in allograft nephropathy (8). Potential explanations for the discrepancies are that different pathomechanisms operate in the various animal models or th...

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

“…50 The estrogen-like antifibrotic effects are possibly related to the reduction in TGF-b expression. [43][44][45]49,50,53,54 It is interesting to note that these reported renoprotective effects of estrogens parallel the findings observed for tamoxifen in this study. 47 All effects of estrogens are mediated via ER, intracellular transcription factors that regulate the transcription of target genes.…”

“…However, modifications of sex hormone status, such as estrogen deficiency induced by ovariectomy, are shown to worsen renal damage and accelerate the progression of renal disease in several models of kidney disease. [42][43][44][45][46] Studies using 17b-estradiol, 2-hydroxyestradiol, or estriol replacement provide evidence that estrogen or estrogen metabolites have a beneficial effect ameliorating renal damage. [43][44][45][46][47][48] For example, the data showed that estrogen or estrogen metabolites reduced albuminuria, attenuated renal lesions, and prevented disease progression in a wide variety of experimental models of renal disease.…”

“…49 The favorable effects of estrogens in the kidney are possibly related to their known effects on mesangial cells, as demonstrated both in vitro and in vivo, by reducing proliferation 50 and synthesis of collagen and other ECM components, 43,47,51,52 which contributes to preventing the development of glomerulosclerosis [42][43][44][45][46][47] and tubulointerstitial fibrosis. [43][44][45]48 In addition, estrogens induce a reduction in PAI-1 levels. 50 The estrogen-like antifibrotic effects are possibly related to the reduction in TGF-b expression.…”

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

“…Time course analysis of podocyte injury revealed that desmin, an early injury marker, 28 was already expressed in some glomeruli of DSHs at 2 weeks of salt loading ( Figure 3A and 3B). We further assessed podocyte damage by transmission electron microscopy ( Figure 3C).…”

“…28 Glomerular B7-1 staining was semiquantitated as the percentage of B7-1-positive glomeruli per total glomeruli counted. Nephrin staining was scored into 0, 0.5ϩ, and 1ϩ, according to the scoring system reported previously with some modification.…”