The Protective Roles And Mechanisms Of IL-6 Receptor Blockade On Diabetic Nephropathy

Background: Chronic inflammation process has been confirmed to play central roles in the pathogenesis and progression of diabetic nephropathy.Interleukin 6(IL-6),as a pleiotro pic cytokine,has been identified as a key mediator in inflammation,immun ity and glucose metabolism.Previous studies have verified that IL-6 participated in the pathophysiological processes of renal innate cell injury,mesangial matrix deposition and int erstitial fibrosis in diabetic conditions.Here,we assessed the protective role s and mechanisms of IL-6 receptor(IL-6R)blockade on diabetic nephropathy.Methods: Twelve-week-old db/db mice were treated with Tocilizumab(a monoclonal antibody against IL-6R),isotype control IgG1,insulin and saline,respectively,with db/m mice as normal control.At the end of the experiment,we evaluated urinary albumin excretion,renal pathological injury,IL-6 signaling pathway,renal proinflammatory cytokine s expression(e.g.MCP-1,P-selectin and TGF-?1),urinary 8-OHdG level and renal NLRP3 inflammasome in each group.Additionally,we not only measured b lood glucose,fasting plasma insulin and glycosylated hemoglobin,but performed glucose tolerance test to evaluate insulin resistance in mice.Results: As compared to db/db+IgG controls,IL-6R blockade reduced urinary albumin excretion and glomerular m esangial matrix accumulation in db/db mice.Additionally,IL-6R blockade could suppress IL-6 signaling pathway and rena l inflammatory cytokines expression including MCP-1,P-selectin and TGF-?1,as well as reduce urinary 8-OHdG level in diabetic mice.Db/db mice exhibited hyperglycaemia,hyperinsulinaemia,elevated glycosylated hemoglobin and insulin resistance,all of whi ch were ameliorated by IL-6R blockade.Furthermore,we provided the demonstration that blockade of IL-6 receptor inhibited NLRP3 inflammasome activation in diabetic nephropathy partly through the regulation of IL-17 A expression.Conclusions: Blockade of IL-6 receptor could ameliorate diabetic kidney injury,and the protective effects might be due to improvement of glucose metabolism and inhibition of NLRP3 inflammasome.Our study revealed the potential clinical value of IL-6R blockade on modulating the dev elopment of diabetic nephropathy.