Renoprotective effects of a selective estrogen receptor modulator, raloxifene, in an animal model of diabetic nephropathy.
OBJECTIVE
Our previous studies have shown that supplementation with 17beta-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-beta) 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-beta: 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.
Dixon
Alexis
A
Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA.
Wells
Corinne C
CC
Singh
Sandhya
S
Babayan
Regina
R
Maric
Christine
C
D000818:Animals; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007668:Kidney / Q000187:drug effects*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*
D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride