Pioglitazone Ameliorates Glomerular NLRP3 Inflammasome Activation In Apolipoprotein E Knockout Mice With Diabetes Mellitus

Objective:The NLRP3 inflammasome plays an important role in the pathogenesis of inflammation in diabetic nephropathy(DN).Pioglitazone(PIO)has been found to exert an anti-inflammatory effect in patients with diabetes mellitus,but it is still unclear whether PIO exhibits a similar effect in DN.We aimed to explore the effect and underlying mechanism of PIO on DN,as well as investigate if NLRP3 is a pharmacologic target of PIO.Methods:A total of 48 apolipoprotiein E apoE-/-mice were divided into 4 groups:apoE-/-,apoE-/-with PIO,diabetic apoE-/-,and diabetic apoE-/-with PIO.Wild type male C57BL/6 mice were used as controls(n = 8 per group).After 8 weeks of PIO treatment,the mouse baseline characteristics and metabolic parameters were determined,and the expression levels of advanced glycation end products(AGEs),receptor for advanced glycation end products(RAGE),NLRP3,nuclear factor-kappa B(NF-?B),caspase-1,interleukin(IL)-18,and IL-1? were assessed by western blot,immunohistochemical staining and enzyme-linked immunosorbent assay(ELISA),respectively.Results:1.Compared to the diabetic ApoE-/-group,PIO treatment decreased blood glucose,cholesterol,serum blood urea nitrogen(BUN),and creatinine levels.PIO not only can improve the metabolism of blood glucose and lipid,but also can delay the decline of effective glomerular filtration rate caused by diabetes.2.Confirmed by PAS staining:compared to the diabetic ApoE-/-group,PIO treatment decreased glomerular mesangial expansion.3.Compared to the diabetic ApoE-/-group,PIO treatment down-regulated expression of AGEs,RAGE,4.Compared to the diabetic ApoE-/-group,PIO treatment down-regulated expression NF-?B,5.Compared to the diabetic ApoE-/-group,PIO treatment down-regulated expression NLRP3,caspase-1,IL-18,and IL-1? levels.Conclusion:Pioglitazone can ameliorate diabetic renal damage,and this effect is related to the inhibition of renal AGE/RAGE axis activation and the down-regulation of NF-?B expression.These effects lead to a decline in NLRP3 levels and downstream secretion of inflammatory cytokines.