Raging hormones: gender and renal disease.

Gender affects the progression of renal disease. In a variety of animal models and in certain human renal diseases, females exhibit a more modest course of kidney disease. Estrogens and testosterone have been implicated in this gender disparity. Doublier and colleagues explore the direct effects of sex hormones on podocyte viability in the α-estrogen receptor knockout (αERKO) mouse. They report that testosterone induces, and estradiol inhibits, podocyte damage in this model.

Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis.

Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.

The effects of hormone replacement therapy on renal function.

This Practice Point commentary discusses a study by Ahmed et al. that evaluated the effects of hormone replacement therapy (conjugated estrogen alone, progestin alone or a combination of progestin and conjugated estrogen) on renal function in elderly community-dwelling postmenopausal women. The authors found that oral estrogen therapy in this population was associated with accelerated decline in kidney function over a 2-year period. In addition, the cumulative amount of estrogen intake was dose-dependently associated with the rate of renal functional decline. This commentary highlights the human and experimental evidence suggesting that endogenous and exogenous estrogen affect renal function, and discusses the possible beneficial or detrimental effects of hormone supplementation on kidney function.

Gender and human chronic renal disease.

BACKGROUND: Gender affects the incidence, prevalence, and progression of renal disease. In animal models of the disease, female sex appears to modify the course of progression. Hormonal manipulation by male or female castration also changes the course of renal disease progression, suggesting direct effects of sex hormones in influencing the course of these maladies. OBJECTIVE: This review examines the pertinent animal and human studies assessing the role of gender, and strives to shed light on the possible physiologic mechanisms underlying the effect of gender, on renal disease progression. METHODS: A summary and evaluation of past and recent studies describing the rate of renal disease progression in animal models and humans as it pertains to gender is provided. In addition, studies elucidating the factors involved in the more modest renal progression rate in females are reviewed and conclusions drawn. Relevant English-language publications were identified by searching the PubMed database from January 1990 until November 2007 using the search terms gender, sex, renal disease, and kidney. RESULTS: In polycystic kidney disease, membranous nephropathy, immunoglobulin A nephropathy, and "chronic renal disease of unknown etiology," men progress at a faster rate to end-stage renal failure than do women. In type 1 diabetes mellitus, there is evidence that males are more likely to manifest signs of renal disease, such as proteinuria. The factors involved in this gender disparity may include diet, kidney and glomerular size, differences in glomerular hemodynamics, and the direct effects of sex hormones. In many, but not all, animal models of renal disease, estrogens slow progression rate. Several studies have recently evaluated the effect of selective estrogen receptor modulators on renal function in humans. CONCLUSION: Further studies assessing the factors involved in the gender disparity in renal disease progression and the effects of hormonal treatments are warranted.

Estradiol reverses renal injury in Alb/TGF-beta1 transgenic mice.

BACKGROUND: Men with chronic renal disease progress more rapidly to renal failure than do women. Tranforming growth factor-beta (TGF-beta) plays a central role in promoting progressive renal injury, in part due to transcriptional effects mediated by cooperation between Smad proteins and the transcription factor Sp1. Estrogen negatively regulates Sp1 activity and reverses the stimulatory effects of TGF-beta on type IV collagen synthesis and cellular apoptosis in cultured mesangial cells. We hypothesized that the ability of estradiol to reverse the effects of TGF-beta underlies gender dimorphism in the progression of chronic renal disease. METHODS: We studied Alb/TGF-beta transgenic mice, which overexpress TGF-beta1 and develop proteinuria and progressive glomerulosclerosis. We implanted a sustained-release estradiol pellet or a placebo pellet into control and Alb/TGF-beta transgenic mice at 2 weeks of age. Animals were sacrificed at 5 weeks, at which time urine, blood, and renal tissue were obtained for study. RESULTS: The sustained-release estradiol pellet achieved a physiologic concentration of estradiol. TGF-beta levels were higher in estradiol-treated mice compared to placebo-treated mice. Proteinuria was reduced in estradiol-treated Alb/TGF-beta mice compared to placebo-treated transgenic mice. Mesangial expansion and closure of capillary loops with enhanced glomerular deposition of type I collagen, type IV collagen, and tissue inhibitor of metalloproteinase (TIMP-2) was observed in glomeruli of placebo-treated transgenic mice. Estrogen therapy reversed these abnormalities. CONCLUSION: Administration of estradiol to Alb/TGF-beta transgenic mice, which overexpress TGF-beta, ameliorated progressive renal injury. The ability of estradiol to reverse the pro-fibrotic effects of TGF-beta, both in vitro and in vivo, may underlie the sexual dimorphism in renal disease progression observed in humans.

The role of gender in the progression of renal disease.

The rate of progression of certain renal diseases in animals is greater in men than in women. In various animal models of renal disease, investigators have concluded that the presence of testosterone explains the worse course in men compared with women, whereas in other diseases, estrogen seems to confer protection for women. The gender disparity in renal disease progression found in animals is seen in certain human renal diseases, including chronic renal disease, membranous nephropathy, immunoglobin A nephropathy, and polycystic kidney disease. In humans, the differences between the genders in renal disease progression cannot be fully explained by differences in blood pressure or serum cholesterol levels. The underlying mechanisms for this gender disparity are potentially related to differences between the sexes in glomerular structure, glomerular hemodynamics, diet, variations in the production and activity of local cytokines and hormones, and/or the direct effect of sex hormones on kidney cells. Further investigation into the contribution of gender to renal disease progression may aid us in developing strategies for slowing this pathological process.

Estradiol reverses TGF-beta1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism.

BACKGROUND: The slower rate of progression of chronic renal disease in women than in men is explained in part by the ability of estradiol to reverse the stimulatory effect of transforming growth factor-beta1 (TGF-beta1) on collagen IV synthesis at the level of casein kinase 2 activation. Casein kinase 2 also phosphorylates and activates the pro-apoptotic protein, p53. We hypothesized that estradiol would reverse TGF-beta1-induced mesangial cell apoptosis by antagonizing the stimulatory effects of TGF-beta1 on casein kinase 2 activity, thereby preventing p53 activation. METHODS: The effects of TGF-beta1 on mesangial cell apoptosis, p53 phosphorylation, Bax and Bcl-2 levels, caspase 9 activity, and cleavage of PARP were examined. The abilities of estradiol and a specific inhibitor of CK2 (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) (DRB) to modulate the effects of TGF-beta1 on these processes were also examined. RESULTS: TGF-beta1 (2 ng/mL), which up-regulates CK2 activity, induces apoptosis in murine mesangial cells together with p53 serine389 phosphorylation, up-regulation of Bax, suppression of Bcl-2, destabilization of mitochondrial permeability transition pores, stimulation of caspase 9 activity and activation of PARP. TGF-beta1-induced p53 activation and all the intermediary steps leading to mesangial cell apoptosis were reversed by estradiol (10-9 mol/L) and by DRB, potent inhibitors of CK2 activity, but not by inhibitors of the p38 MAPK, ERK or JNK signaling cascades. In contrast, TGF-beta1 failed to induce apoptosis in p53 knockout mesangial cells. CONCLUSIONS: Our data suggest that CK2 mediates the stimulatory effects of TGF-beta1 on mesangial cell apoptosis via a p53-dependent mechanism. The ability of estradiol to reverse TGF-beta1-induced apoptosis may contribute to the protective effects of female gender on the course of chronic renal disease.

Effects of sex on renal structure.

AIMS: There are few data examining differences in renal structure between the sexes. Elucidation of the mechanisms responsible for the observed effects of sex on the progression of chronic renal disease requires knowledge of the effects of sex on renal structure. RESULTS: Although we found that male kidneys weigh more than female kidneys, sex is not an independent determinant of kidney weight. The increased kidney weight seen in men is solely dependent on their greater body surface area. We found no difference in glomerular number between men and women. Although men had larger glomeruli than women, sex is not an independent determinant of glomerular volume. The occurrence of larger glomeruli in men is solely dependent on their greater body surface area. Similarly, the greater total glomerular volume seen in men as compared to women reflects increased kidney weight in men. Sex is not an independent determinant of total glomerular volume. CONCLUSIONS: These findings do not support the hypothesis that renal structural differences contribute to sex-related differences in the rate of progression of chronic renal disease.

Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2.

The accumulation of extracellular matrix in the glomerular mesangium reflects the net balance between the synthesis and degradation of matrix components. We have shown that estradiol suppresses the synthesis of types I and IV collagen by cultured mesangial cells (Kwan G, Neugarten J, Sherman M, Ding Q, Fotadar U, Lei J, and Silbiger S. Kidney Int 50: 1173-1179, 1996; Neugarten J, Acharya A, Lei J, and Silbiger S. Am J Physiol Renal Physiol 279: F309-F318, 2000; Neugarten J, Medve I, Lei J, and Silbiger SR. Am J Physiol Renal Physiol 277: F1-F8, 1999; Neugarten J and Silbiger S. Am J Kidney Dis 26: 147-151, 1995; Silbiger S, Lei J, and Neugarten J. Kidney Int 55: 1268-1276, 1998; Silbiger S, Lei J, Ziyadeh FN, and Neugarten J. Am J Physiol Renal Physiol 274: F1113-F1118, 1998). In the present study, we evaluated the effects of sex hormones on the activity of matrix metalloproteinase-2 (MMP-2) in murine mesangial cells, the synthesis of which is regulated by the transcription factor activator protein-2 (AP-2). Estradiol stimulated MMP-2 activity by increasing MMP-2 protein levels in a dose-dependent manner. These effects occurred at physiological concentrations of estradiol and were receptor mediated. Estradiol also increased AP-2 protein levels and increased binding of mesangial cell nuclear extracts to an AP-2 consensus binding sequence oligonucleotide. The ability of estradiol to increase AP-2 protein expression, AP-2/DNA binding activity, MMP-2 protein expression, and metalloproteinase activity was reversed by PD-98059, a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade. We conclude that estradiol upregulates the MAPK cascade, which in turn stimulates the synthesis of AP-2 protein. The resultant increased AP-2/DNA binding activity leads to increased synthesis of MMP-2 and increased metalloproteinase activity. Stimulation of metalloproteinase activity by estradiol may contribute to the protective effect of female gender on renal disease progression.

Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.

There is previously published evidence that male gender is associated with a more rapid rate of progression of nondiabetic chronic renal disease. However, some investigators have concluded that no such association exists. To help resolve this issue, a meta-analysis was performed using 68 studies that met defined criteria and contained a total of 11,345 patients to evaluate the effect of gender on the progression of nondiabetic chronic renal disease. The results indicate that men with chronic renal disease of various etiologies show a more rapid decline in renal function with time than do women.