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17-Estradiol attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor- protein expression and signaling

¹Department of Medicine and ²Center for the Study of Sex Differences: in Health, Aging, and Disease, Georgetown University Medical Center, Washington, DC

Submitted 14 February 2007 ; accepted in final form 2 August 2007

We previously showed that supplementation with 17-estradiol (E₂) from the onset of diabetes attenuates the development of diabetic renal disease. The aim of the present study was to examine whether E₂ can also attenuate the disease process once it has developed. The present study was performed in nondiabetic and streptozotocin-induced diabetic Sprague-Dawley rats. E₂ supplementation began after 9 wk of diabetes and continued for 8 wk. Diabetes was associated with an increase in urine albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, renal cortical collagen type I and IV, laminin, plasminogen activator inhibitor-1, tissue inhibitors of metalloproteinase-1 and -2, transforming growth factor (TGF)-, TGF- receptor type I and II, Smad2/3, phosphorylated Smad2/3, and Smad4 protein expression, and CD68-positive cell abundance. Decreases in matrix metalloproteinase (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 developed by 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 may be novel targets for the treatment and prevention of diabetic renal disease.

diabetes; estradiol; fibrosis; glomerulosclerosis; transforming growth factor-; Smads

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