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Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2. Am J Physiol Renal Physiol 282: F164-F169, 2002. First published August 30, 2001; 10.1152/ajprenal.00318.2000.--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. gelatinase; estrogen; extracellular signal-regulated kinase; mitogen-activated protein kinase; gender

Fetal calf serum (FCS) stimulated rat mesangial cells to synthesize alpha1 type IV collagen. Transforming growth factor-beta (TGF-beta) mediates genetic transcription of the type IV collagen gene via a mechanism dependent on platelet-derived growth factor (PDGF). Studies using neutralizing antibodies confirmed the role of TGF-beta and PDGF in the FCS-stimulated synthesis of collagen by mesangial cells. Estradiol was shown to inhibit the synthesis of collagen in this cell line.

Neugarten, Joel, Anjali Acharya, Jun Lei, and Sharon Silbiger. Selective estrogen receptor modulators suppress mesangial cell collagen synthesis. Am J Physiol Renal Physiol 279: F309-F318, 2000.--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. Type I collagen synthesis was also suppressed by LY-117018 in a dose-dependent manner with a potency identical to that of estradiol but greater than that of tamoxifen. Genistein, which selectively binds to estrogen receptor-[Beta] in nanomolar concentrations, suppressed type I and type IV collagen synthesis, suggesting that estrogen receptor-[Beta] mediates the effects of estrogen on collagen synthesis. Because matrix accumulation is central to the development of glomerulosclerosis, second-generation SERMs may prove clinically useful in ameliorating progressive renal disease without the adverse effects of estrogen on reproductive tissues. estradiol; angiotensin II; transforming growth factor-[[Beta].sub.1]; endothelin

Neugarten, Joel, Ildiko Medve, Jun Lei, and Sharon R. Silbiger. Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade. Am. J. Physiol. 277 (Renal Physiol. 46): F875-F881, 1999.--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.sup.-10] to [10.sup.-7] M) upregulated the MAP kinase pathway in murine mesangial cells grown in the presence of serum in a dose-dependent manner. Activation was evident by 1 min, peaked at 10 rain, and was completely dissipated by 2 h. In contrast, estradiol had no significant effect on total (phosphorylated + unphosphorylated) p44 extracellular signal-related protein kinase (ERK) or p42 ERK. Nuclear extracts isolated from mesangial cells treated with estradiol showed increased binding to a consensus sequence AP-1 binding oligonucleotide in gel shill assays. In contrast, nuclear extracts from cells exposed to PD-98059, a highly selective inhibitor of MAP kinase-ERK kinase 1 (MEK1) and MEK2, showed reduced binding. In addition, PD-98059 antagonizes the enhanced binding induced by estradiol. Estradiol ([10.sup.-9] M) suppressed mesangial cell type I collagen synthesis (37.8 [+ or -] 2.4%, expressed as a percentage of control values, P [is less than] 0.001 vs. control). In contrast, PD-98059 increased type I collagen synthesis (344.6 [+ or -] 98.8, P [is less than] 0.01) and reversed the suppression of type I collagen synthesis induced by estradiol. The effects of estradiol, PD-98059, and PD-98059 plus estradiol on type I collagen protein synthesis were closely paralleled by their effects on steady-state levels of mRNA for the [[Alpha].sub.1] chain of type I collagen. These data suggest that estradiol suppresses type I collagen synthesis via upregulation of the MAP kinase cascade, leading to stimulation of AP-1 activity. gender; sex hormones; matrix proteins; glomerular mesangium; mitogen-activated protein kinase

Examines the interaction between estradiol and transforming growth factor-beta1 on collagen synthesis. Methodology; Graphical representations of the study.

Examines the hypothesis that fetal calf serum (FCS) stimulates murine mesangial cell ...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 mechanism. How the study was done; Results of the study; Discussion of the results.

The authors discuss the process of creating the Step 1 Guidance Program in 2010 to help medical students in the preparation of United States Medical Licensing Examination. They mention that they developed the program to enable free flow of information from senior students to junior students and another aim was to motivate students and reduce anxiety. They reveal that a survey was conducted on the student of the Albert Einstein College of Medicine to know students' views on study resources.

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.