Resveratrol Prevention Of Diabetic Nephropathy Is Associated With The Suppression Of Renal Inflammation And Mesangial Cell Proliferation: Possible Roles Of Akt/NF-κB Pathway

Glomerular mesangium expansion is one of the characters of early DN.Accumulated data suggest the predicted evolution of diabetic glomerulopathy iscomprised of an early, transient mesangial cell proliferation and subsequenthypertrophy of these cells that herald the slow progression intoglomerulosclerosis. In addition, inflammation is also an importantpathophysiological factor in the development and progression of DN. In thepresent study, we aimed to determine whether resveratrol (RSV) treatmentattenuated renal inflammation and mesangial cell proliferation under diabeticcondition both in vivo and in vitro. By usingAkt activity inhibitors, we havemechanistically defined whether the protective effect of RSV on DN was due toAkt-dependent depression of NF-κB.To investigate the protection of RSV in diabetes associated with kidneyin ammation and cell proliferation, rat mesangial cell andstreptozotocin-induced type1diabetes mouse model were used. In vitro, RSVattenuated high glucose induced plasminogen activator inhibitor (PAI-1)expression and mesangial cell proliferation, as well asAkt and nuclear factor-kappa B (NF-κB) activation. The similar results were recaptured in theexperiment withAkt inhibitors. In vivo, mice were divided into three groups:control group, diabetes mellitus (DM) group and RSV-treated DM group.Compared with control group, albumin to creatinine ratio was increased in DMgroup, but not in RSV-treated DM group. Furthermore, the increased expressionof PAI-1and intercellular adhesion molecule-1in diabetic renal cortex were alsoreduced by RSV administration. Besides, the kidney p-Akt/Akt ratio and NF-κBwere significantly increased in DM group; however, these changes werereversed in RSV-treated DM group.Additionally, immunohistochemistry resultsindicated that RSV treatment reduced the density of proliferating cell nuclearantigen-positive cells significantly in glomeruli of diabetic mice. These resultssuggest that RSV prevents diabetes induced renal in ammation and mesangialcell proliferation possibly throughAkt/NF-κB pathway inhibition.Collectively, our results showed augmented p-Akt/Akt in HG treatedmesangial cells, and such induction seemed to be attenuated by RSV andAktactivity inhibitors. Furthermore, in our in vivo study, we demonstrated p-Aktincreased in whole kidney lysates from3-month STZ-induced diabetes mice andRSV treatment downregulated p-Akt expression. Since activeAkt is one ofphysiological activators of NF-κB, it is possible that RSV inhibited NF-κBactivity via suppression ofAkt activity and, consequently, attenuatedin ammation and renal mesangial cell proliferation to protect DN.