Renoprotective Effects of a Selective Estrogen Receptor Modulator, Raloxifene, in an Animal Model of Diabetic Nephropathy

Abstract

Background/Aims: Our previous studies have shown that supplementation with 17β-estradiol (E₂) from the onset of diabetes attenuates diabetic nephropathy. However, E₂ is accompanied by feminizing effects as well as adverse side effects on other organs. The current study examined the renoprotective effects of a selective estrogen receptor modulator, raloxifene (RAL), in an experimental model of diabetic nephropathy. RAL activates estrogen receptors and estrogen-receptor-mediated cellular events without the side effects of E₂. Methods: The study was performed in Sprague-Dawley nondiabetic (ND), streptozotocin-induced diabetic (D) and streptozotocin-induced D + RAL rats (n = 6/group). Results: After 12 weeks of treatment, D was associated with increased urine albumin excretion (ND: 4.2 ± 0.4; D: 41.3 ± 9.0 mg/day), glomerulosclerosis [glomerulosclerotic index; ND: 0.26 ± 0.04; D: 1.86 ± 0.80 arbitrary units (AU)], tubulointerstitial fibrosis (tubulointerstitial fibrosis index; ND: 0.37 ± 0.05; D: 2.12 ± 0.50 AU), increased collagen type I [ND: 1.31 ± 0.07; D: 4.65 ± 0.09 relative optical density (ROD)], collagen type IV (ND: 0.64 ± 0.03; D: 1.37 ± 0.11 ROD) and transforming growth factor beta (TGF-β) protein expression (ND: 0.65 ± 0.08; D: 1.25 ± 0.10 ROD), increased density of CD68-positive cells (ND: 1.37 ± 3.02; D: 29.2 ± 1.74 cells/mm²) and increased plasma levels of interleukin-6 (ND: 14.8 ± 5.0; D: 51.3 ± 14.0 pg/ml). Treatment with RAL partially or fully attenuated these processes (urine albumin excretion: 21.0 ± 5.0 mg/day; glomerulosclerotic index: 0.40 ± 0.06 AU; tubulointerstitial fibrosis index: 0.20 ± 0.04 AU; collagen type I: 2.55 ± 0.49 ROD; collagen type IV: 0.70 ± 0.09 ROD; TGF-β: 0.91 ± 0.08 ROD; CD68: 6.03 ± 2.38 cells/mm²; interleukin-6: 31.2 ± 5.0 pg/ml). Conclusions: Our data indicate that treatment with RAL attenuates albuminuria and renal structural changes associated with diabetes.