Effects Of Resveratrol On Renal Hypertrophy In Early-stage Diabetes And The Underlying Mechanisms

[Abstract] Background Recent studies suggest the involvement of the adenosine monophosphate-activated serine/threonine protein kinase (AMPK) pathway in the pathogenesis of diabetic nephropathy (DN). Resveratrol, an agent that activates AMPK, may have the potential to protect against the development of DN. This study was designed to investigate the therapeutic effects of resveratrol on renal hypertrophy in early-stage diabetes and the underlying mechanisms. Method (1) Sprague-Dawley (SD) male rats were divided into a normal control(NC) group (n=6), normal control treated with resveratrol (NR) group (n=6) and a diabetic group (n=13) at random. Diabetes was induced by intraperitoneal injection of STZ (60 mg kg-1, dissolved in ice cold sodium citrate buffer, 0.01 M, pH 4.4) after 12 h of food deprivation. Rats with plasma glucose level >250 mg/dL were included in the study as diabetic rats. Age matched normal control rats received sodium citrate buffer. After 10 weeks, diabetic rats were divided into two groups, namely diabetic control (DM) without treating (n=7) and diabetic rats treated with Resveratrol (DR) orally (n=6). Starting from week 11 till week 14, the NC and DC groups received vehicle of Resveratrol. NR and DR group received a suspension of Resveratrol (10 mg kg-1 b.w. day-1) orally. At the end of 14 weeks, the rats in different groups were sacrificed for kidney and blood samples. A slice of renal cortex at the pole was embedded in paraffin or flash-frozen in liquid nitrogen for light microscopy and subsequent analyses. Molecular and structural changes involved in the pathogenesis of DN were tested in a rat model of earlystage diabetes. (2) Renal mesangial cells (RMCs) were cultured in media containing different concentrations of glucose with or without resveratrol. Cellular DNA synthesis was assayed by measuring 3 H-thymidine incorporation. The phosphorylation status of AMPK, eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and phosphoribosomal protein S6 (S6) was analyzed by Western blot. Results (1) Resveratrol reduced plasma creatinine and urinary albumin excretion and attenuated renal hypertrophy without affecting blood glucose levels. Moreover, resveratrol activated AMPK and inhibited phosphorylation of 4E-BP1 and S6 in diabetic rat kidneys. (2) In vitro, resveratrol blocked high glucose-induced dephosphorylation of AMPK and phosphorylation of 4E-BP1 and S6 and strongly inhibited both the DNA synthesis and proliferation of RMCs. Conclusion These dates indicate that Resveratrol inhibited RMCs proliferation and ameliorated rat renal hypertrophy, the mechanism involved might be the activation of AMPK and the reduced expressions of the S6 and 4E-BP1 protein phosphorylation.