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17-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy

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

Submitted 27 May 2004 ; accepted in final form 23 September 2004

The protective factor of female gender appears to be lost in diabetes; the incidence of diabetes and its complications, including diabetic nephropathy, are equal in women and men. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and replacement with 17-estradiol (OVX+E₂) on renal function and pathology in the nondiabetic (ND) and streptozotocin (STZ)-induced diabetic (D) rat kidneys for 12 wk. Diabetes was associated with an increase in urine albumin excretion (UAE; ND, 0.39 ± 0.03; D, 5.9 ± 0.8 mg/day; P < 0.001), decrease in creatinine clearance (CrCl; ND, 0.69 ± 0.03; D, 0.43 ± 0.09 mg·min^–1·100 g body wt^–1; P < 0.05), increase in the index of glomerulosclerosis [GSI; ND, 0.01 ± 0.01; D, 0.15 ± 0.04 arbitrary units (AU); P < 0.01], tubulointerstitial fibrosis (TIFI; ND, 0.04 ± 0.04; D, 0.68 ± 0.2 AU; P < 0.01), and transforming growth factor- (TGF-) protein expression (ND, 0.61 ± 0.02; D, 1.25 ± 0.07 AU; P < 0.01). In the D group, the severity of these changes was augmented with OVX (UAE, 8.1 ± 0.6 mg/day; CrCl, 0.40 ± 0.04 mg·min^–1·100 g body wt^–1; GSI, 0.29 ± 0.04 AU; TIFI, 0.90 ± 0.06 AU; TGF-, 1.26 ± 0.10 AU), whereas E₂ replacement attenuated these changes (UAE, 6.3 ± 0.8 mg/day; CrCl, 0.66 ± 0.03 mg·min^–1·100 g body wt^–1; GSI, 0.06 ± 0.02 AU; TIFI, 0.36 ± 0.08 AU; TGF-, 0.57 ± 0.08 AU). We conclude that E₂ deficiency increases the severity of renal disease in a diabetic animal model and that E₂ replacement is renoprotective by attenuating the decline in renal function and pathology associated with diabetes.

diabetes; kidney; estrogen; extracellular matrix; fibrosis

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