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.

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.

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.

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.

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.

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.

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.

Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production.

We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic mice overexpressing hIL-17E using an apolipoprotein E (ApoE) hepatic promoter.

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.

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.

Protein kinase CK2 mediates TGF-beta1-stimulated type IV collagen gene transcription and its reversal by estradiol.

Background: We have previously shown that the transcription factor Sp1 mediates the stimulatory effects of transforming growth factor-beta1 (TGF-beta1) on type IV collagen gene transcription and protein synthesis, and that estradiol reverses these effects by down-regulating Sp1 activity. Protein kinase casein kinase II (CK2) phosphorylates Egr-1 and prevents its binding to Sp1. We hypothesized that TGF-beta1 stimulates CK2 activity, which in turn activates type IV collagen gene transcription via increased availability of free Sp1.

Evidence that the protein tyrosine phosphatase (PC12,Br7,Sl) gamma (-) isoform modulates chondrogenic patterning and growth.

One of the earliest events in bone morphogenesis is the condensation of embryonic mesenchymal cells into chondroblasts and their subsequent proliferation and differentiation into chondrocytes. During this time, certain signaling cascades operate to establish proper patterning and differentiation of the cartilaginous skeleton. Characterization of the signaling pathways involved in these processes remains to be accomplished.

Selective estrogen receptor modulators suppress mesangial cell collagen synthesis.

Estrogen receptor modulators (SERMs) are "designer drugs" that exert estrogen-like actions in some cells but not in others. We examined the effects of the SERMs LY-117018 (an analog of raloxifene) and tamoxifen on mesangial cells synthesis of type I and type IV collagen. We found that LY-117018 and tamoxifen suppressed mesangial cell type IV collagen gene transcription and type IV collagen protein synthesis in a dose-dependent manner, with a potency identical to that of estradiol.

Protein tyrosine phosphatase (PC12, Br7,S1) family: expression characterization in the adult human and mouse.

Protein tyrosine phosphatases (PTPs) play important roles in modulating signals transduced by tyrosine kinases. Certain phosphatases have been implicated as having important roles in embryonic development as well as in adult physiology. Although both kinases and phosphatases are equally important in regulating signal transduction, phosphatases as a group have not been well characterized.

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.

Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade.

We have previously shown that estradiol suppresses the synthesis of type I collagen by murine mesangial cells grown in the presence of serum via activation of the transcription factor activator protein-1 (AP-1). We hypothesized that estradiol upregulates AP-1 via activation of the mitogen-activated protein (MAP) kinase cascade, a signal transduction pathway that regulates AP-1 activity. Estradiol (10(-10) to 10(-7) M) upregulated the MAP kinase pathway in murine mesangial cells grown in the presence of serum in a dose-dependent manner.

Glomerulosclerosis in aging humans is not influenced by gender.

Aging male rats develop progressive glomerulosclerosis, proteinuria, and loss of renal function, whereas females are remarkably resistant to the development of these abnormalities. Although sex hormones appear to contribute to gender-related differences in the development of glomerulosclerosis in aging rats, it is not clear that sexual dimorphism characterizes glomerular obsolescence in aging humans. To study this question further, the glomerular histology of males and females ranging in age from infancy to 90 years was compared in 250 autopsy specimens.

Estradiol suppresses type I collagen synthesis in mesangial cells via activation of activator protein-1.

Background: Estradiol suppresses the synthesis of type I collagen by murine mesangial cells. However, neither the alpha 1(I) nor the alpha 2(I) collagen gene contains an estrogen-response element. Because estradiol modulates the transcription of several genes that lack an estrogen-response element but contain a regulatory activator protein-1 (AP-1) binding motif, we hypothesized that AP-1 may mediate estradiol-induced suppression of type I collagen synthesis.

Estradiol reverses TGF-beta1-stimulated type IV collagen gene transcription in murine mesangial cells.

We have previously shown that estradiol suppresses types I and IV collagen synthesis by mesangial cells grown in the presence of serum. In the present study, we examined the interaction between estradiol and transforming growth factor-beta (TGF-beta) on collagen IV synthesis. In a luciferase reporter gene construct containing the type IV collagen promoter and 1-chain regulatory sequences, we found that TGF-beta1 (2 ng/ml) stimulated alpha1-collagen IV gene transcription in serum-free media (140.

Serum-stimulated alpha 1 type IV collagen gene transcription is mediated by TGF-beta and inhibited by estradiol.

We examined the hypothesis that fetal calf serum (FCS) stimulates murine mesangial cell alpha 1 type IV collagen (COL4A1) gene transcription by increasing autocrine production of transforming growth factor-beta (TGF-beta) through a platelet-derived growth factor (PDGF)-dependent mechanisms. PDGF-stimulated COL4A1 gene transcription was inhibited by neutralizing antibody to TGF-beta (119.3 +/- 3.

Sex hormones and renal nitric oxide synthases.

The present study was undertaken to determine whether sex hormones influence nitric oxide synthase levels in the kidney. Five groups of rats were studied: males, castrated males, females, oophorectomized females, and oophorectomized females receiving estradiol replacement therapy. Endothelial nitric oxide synthase (eNOS) levels in the kidney were measured by Western blotting.

Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells.

Polycystic kidney disease progresses more rapidly in men than in women. To investigate the basis for this sexual dimorphism, we exposed Madin-Darby canine kidney (MDCK) cells grown on collagen-coated cell culture inserts to control media, or to estradiol or testosterone (1 nM-1 microM). Compared to control and estradiol-treated cells, testosterone stimulated fluid secretion in a dose-dependent manner, enhancing fluid secretion 4.