Abstract-Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (nϭ10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-␤ protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications. (Hypertension. 2008;51:1218-1224.)Key Words: diabetes Ⅲ kidney Ⅲ sex hormones Ⅲ glomerulosclerosis Ⅲ tubulointerstitial fibrosis E pidemiological studies show that the incidence and the rate of progression of nondiabetic renal disease are greater in men compared with age-matched women. 1,2 These observations lead to the belief that the male sex is a risk factor and/or that the female sex is a protective factor against the development of renal disease. In the setting of diabetes, however, this relationship is not so clear. Although some studies indicate that the male sex is still a risk factor for the development of diabetic nephropathy and progression to end-stage renal disease, 3,4 other studies suggest either no difference 5,6 or that females progress at a faster rate. 7,8 The actual truth is that the existing data are inadequate for the precise determination of whether sex differences, which clearly exist in nondiabetic renal disease, exist or "disappear" in the setting of diabetes.Our previous studies have shown that diabetes is associated with reduced plasma levels of estradiol in the female streptozotocin (STZ)-induced diabetic rat. 9 Supplementation of estradiol in these animals either from the onset 10,11 or 2 months after the induction of diabetes 12 attenuates the development of renal disease. Clinical studies indicate that diabetes is associated with decreased testosterone levels in men with diabetes, 13,14 suggesting that testosterone deficiency may contribute or at least be associated with the development of diabetic renal disea...

Omega-3 polyunsaturated fatty acids (n-3 PUFA) show beneficial effects in cardiovascular disease, IgA, and diabetic nephropathy; however, the mechanisms underlying these benefits are unknown. The study was performed in male Sprague-Dawley rats randomly divided into four treatment groups: nondiabetic (ND), streptozotocin-induced diabetic (D), diabetic and fed a high n-3 PUFA diet (D+canola), and diabetic and fed a high n-6 (omega-6) PUFA diet (D+corn). Study treatments were carried out for 30 wk. D+canola significantly decreased diabetes-associated increases in urine albumin excretion (ND 17.8 +/- 6.4; D 97.3 +/- 9.4; D+canola 8.3 +/- 2.2 mg/day); systolic blood pressure (ND 153 +/- 9; D 198 +/- 7; D+canola 162 +/- 9 mmHg); glomerulosclerosis (ND 0.6 +/- 0.2; D 1.8 +/- 0.2; D+canola 0.8 +/- 0.1 AU); and tubulointerstitial fibrosis in the renal cortex (ND 1.2 +/- 0.2; D 2.0 +/- 0.2; D+canola 1.1 +/- 0.1) and the inner stripe of the outer medulla (ND 1.0 +/- 0.2; D 2.1 +/- 0.2; D+canola 1.1 +/- 0.2 AU). D+corn also exerted renoprotection, but not to the same degree as D+canola (urine albumin excretion, 33.8 +/- 6.1 mg/day; systolic blood pressure, D+corn 177 +/- 6 mmHg; glomerulosclerosis, D+corn 1.2 +/- 0.3 AU; cortical tubulointerstitial fibrosis, D+corn 1.6 +/- 0.1 AU; medullary tubulointerstitial fibrosis, D+corn 1.5 +/- 0.1 AU). In addition, D+canola attenuated D-associated increase in collagen type I and type IV, IL-6, MCP-1, transforming growth factor-beta, and CD68 expression. These observations indicate a beneficial effect of high dietary intake of n-3 PUFA in reducing diabetic renal disease.

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