Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Abstract

Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. The responsiveness to estrogens could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. This study was undertaken to determine whether the intensity of the sclerotic response was modified by the estrogen status in sclerosis-prone ROP Os/؉ mice. Ovariectomized ROP Os/؉ mice developed more severe renal dysfunction and glomerulosclerosis than intact, ie, estrogen sufficient agematched female mice. Ovariectomized ROP Os/؉ exhibited increased accumulation of extracellular matrix, predominantly of laminin, and a marked distortion of the glomerular architecture. We found an increase in macrophage infiltration in the mesangium of ovariectomized ROP Os/؉. Estrogen deficiency decreased glomerular estrogen receptor expression in ROP Os/؉ mice, which we had previously found to be low in the parental ROP strain. Thus, although physiological estrogen levels in young ROP Os/؉ mice could not prevent the development of glomerulosclerosis, estrogen deficiency accelerated the progression of glomerular scarring in this mouse strain. This suggests that estrogen replacement will slow but not prevent the progression of glomerulosclerosis. It underscores the importance of the genetic composition of individuals that determines the susceptibility to diseases as well as the response to treatment. Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. This is suggested by data from the United States Renal Data System, which show that the female to male ratio of patients with end-stage renal disease because of diabetes increases sharply in the postmenopausal age groups, especially of those from ethnic minorities. 1 The United States Renal Data System data as well as additional genetic and epidemiological studies also suggest that genetic factors play an important role in the susceptibility to develop glomerulosclerosis and the progression to end-stage renal disease. 2,3 The responsiveness to estrogens, which is primarily determined by the level of estrogen receptor (ER) expression, 4 could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. We have previously shown that the renal glomerulus is a direct target tissue for estrogens. 5,6 Human and mouse mesangial cells, which play a central role in the pathogenesis of glomerulosclerosis, express both ER subtypes ␣ and ␤. 5 We reported that these ERs were transcriptionally active and that estrogens positively regulated ER expression in mesangial cells. 5 We also found that estrogens provided protection from glomerulosclerosis by regulating genes involved in extracellular matrix (ECM) turnover in a manner leading to the prevention of ECM accumulation in the mesangium. 5,6 Estrogen treatment increased the expression and activity of matrix metalloproteinase (MMP)-9 in mesangial cells isolated from glomeruloscler...

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

“…Furthermore, we show that the activities of MMP-9 and MMP-2 are increased with E 2 replacement, suggesting that E 2 promotes ECM degradation. Our findings support previous studies, which have reported a similar renoprotective role of estrogen in sclerosis-prone mice (26), in the remnant kidney model (45), and in cultured mesangial cells (27) via similar mechanisms. It will be interesting in future studies to also examine the role of testosterone, as some studies indicate that it is not only the estrogen-deficient state that affects renal disease progression but also the change in ratio of estrogen to testosterone after estrogen deficiency (46).…”

“…The age-related changes in BP in this animal thus correlate with the changes in renal pathology, suggesting that the renoprotective effects of E 2 replacement may be mediated via its effects on BP. However, several studies suggest that estrogens exert a renoprotective effect independently of their BP-lowering effects (3,26) by reducing cell death by apoptosis and increasing ECM degradation. Studies in this laboratory have shown that, in a STZ model of diabetes, E 2 replacement reduces renal collagen type IV synthesis and tubulointerstitial fibrosis without an effect on BP (53).…”

“…E 2 inhibits apoptosis in mesangial cells, increases the expression of extracellular matrix (ECM) degrading metalloproteinases, and reduces collagen type I and type IV synthesis (25)(26)(27). Few studies, however, have investigated the role of E 2 on the aging kidney.…”

Estrogens and the diabetic kidney

“…In both the diabetic and nondiabetic kidney, E 2 attenuates glomerulosclerosis and tubulointerstitial fibrosis by reducing synthesis of type I and type IV collagen, increasing expression of matrix metalloproteinases, and inhibiting apoptosis. 60,61,[68][69][70] Furthermore, E 2 decreases the expression of transforming growth factor-β, angiotensin AT1 receptor and endothelin-1, all of which stimulate abnormal cell growth and extracellular matrix metabolism and contribute to the vascular dysfunction associated with renal disease. 60,71-74 E 2 has also been shown to upregulate nitric oxide synthase activity and vascular endothelial growth factor expression in the glomerulus.…”

Differential Effects of Continuous and Intermittent 17β-Estradiol Replacement and Tamoxifen Therapy on the Prevention of Glomerulosclerosis

“…6 -8 Female ROP Os/ϩ mice develop GS during their reproductive period of life and are, therefore, considered sclerosis-prone. 9 However, estrogen deficiency, induced by ovariectomy, accelerates glomerular dysfunction and scarring in young ROP Os/ϩ mice. 9 This suggests that endogenous estrogens only partially protect this mouse strain from the development of GS.…”