Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Abstract

Abstract. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17␤-estradiol (E 2 ) replacement (OVXϩE 2 ) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-␤ (TGF-␤), 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 Ϯ 0.09 versus 12M, 1.43 Ϯ 0.17; P Ͻ 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 Ϯ 4.9; P Ͻ 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 Ϯ 0.34; CTIFI, 74.4 Ϯ 9.2; P Ͻ 0.01 versus Intact at 12M) and attenuated with E 2 replacement ([GSI], 1.09 Ϯ 0.09; CTIFI, 49.2 Ϯ 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 Ϯ 6.7; OVX, 277.4 Ϯ 9.6 AU; P Ͻ 0.01), increased expression of TGF-␤ (Intact, 85.0 Ϯ 23.0; OVX, 178.0 Ϯ 20.5 AU; P Ͻ 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 Ϯ 0.8; OVX, 2.4 Ϯ 0.6 AUC; P Ͻ 0.01). E 2 replacement opposed these effects (laminin, 229.9 Ϯ 6.2 AU; TGF-␤, 101.3 Ϯ 25.2 AU; MMP-9, 5.2 Ϯ 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 Ϯ 0.01; OVX, 0.22 Ϯ 0.01; OVXϩE 2 , 0.28 Ϯ 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 Ϯ 2.1; OVX, 32.6 Ϯ 5.1; OVXϩE 2 , 24.3 Ϯ 2.4 mg/dl). The authors conclude that E 2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.The rate of progression of cardiovascular and renal disease and hypertension increases with age and is lower in premenopausal women compared with age-matched men (1-3). Interestingly, a re-evaluation of the Modification of Diet in Renal Disease (MDRD) study showed that the differences in the rate of decline of renal function between men and women is reduced after age 52 yr (their dividing point) (4), suggesting that menopause may affect the progression of renal disease in women; however, no studies to date have clearly demonstrated this point, suggesting that our understanding of the contribution of ovarian hormones to the development of age-related disease processes remains unclear. The Women's Health Initiative (WHI) reported that hormone replacement therapy with the estrogen-progesterone combination Prempro (conjugated equine estrogen and progestin) causes a slight increase in the risk of cardiovascular disease in a large population of postmenopausal women (5,6). However, numerous studies indicate that estrogen alone has cardiovascular protective effects. Estrogen improves serum lipid levels, increases end...

Postmenopausal Status as Independent Risk Factor for Metabolic Syndrome

“…171 Accordingly, transdermal administration of 17β-estradiol has been shown to effectively reduce salt sensitivity in postmenopausal women. 172 These observations are further supported by preclinical work of Maric et al 173 using ovariectomized Dahl rats as an animal model of postmenopausal salt-sensitive hypertension. In these animals, 17β-estradiol attenuates age-related renal dysfunction.…”

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

“…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.…”

Sex differences in the fetal programming of hypertension

“…Estradiol is associated with protective cardio-renal effects in many animal models of hypertension (67,68,70) and the deleterious effects of ovariectomy such as induced hypertension, renal injury, or endothelial dysfunction are reversed with estradiol therapy (70,71). Therefore, the cardio-renal protective effect of estradiol appears to be complex and includes a wide range of regulatory systems.…”