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-estradiol attenuates diabetic kidney disease via regulating extracellular matrix and transforming growth factor-beta protein expression and signaling
1 Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia, United States
2 Medicine, Georgetown University Medical Center, Washington, District of Columbia, United States
* To whom correspondence should be addressed. E-mail: cm255{at}georgetown.edu.
We have previously shown that supplementation with 17
-estradiol (E2) from the onset of diabetes attenuates the development of diabetic renal disease. The aim of this study was to examine if E2 can also attenuate the disease process once it has already developed. The study was performed in non-diabetic and streptozotocin-induced diabetic Sprague-Dawley rats. E2 supplementation began after 9 weeks of diabetes for further 8 weeks. Diabetes was associated with an increase in urine albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, renal cortical collagen type I, collagen type IV laminin, PAI-1, TIMP-1, TIMP-2, TGF-, TGF-RI, TGF-RI, Smad2/3, pSmad2/3 and Smad4 protein expression and CD68-positive cells abundance. Decreases in MMP-2 protein expression and activity and decreases in Smad6 and Smad7 protein expression were also associated with diabetes. E2 supplementation completely or partially attenuated all these changes, except Smad4 and fibronectin, on which E2 supplementation had no effect. These data suggest that E2 attenuates the progression of diabetic renal disease once it has already developed via regulating extracellular matrix, TGF- and expression of its downstream regulatory proteins. These findings support the notion that sex hormones in general, and E2 in particular, are important regulators of renal function and that they may be novel targets for the treatment and prevention of diabetic renal disease.
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