Pioglitazone ameliorates glomerular NLRP3 inflammasome activation in apolipoprotein E knockout mice with diabetes mellitus

by Yao Wang, Bo Yu, Li Wang, Ming Yang, Zhiyin Xia, Wei Wei, Fengyu Zhang, Xiaochen Yuan

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.

We divided 48 apolipoprotein E (apoE) (-/-) mice 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, we examined the baseline characteristics and metabolic parameters of each group, and we used enzyme-linked immunosorbent assay (ELISA), western blot, and immunohistochemical staining to evaluate the expression levels of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), NLRP3, nuclear factor—kappa B (NF-κB), caspase-1, interleukin (IL)-18, and IL-1β in each group.

Compared to the diabetic apoE (-/-) group, PIO treatment decreased blood glucose, cholesterol, serum blood urea nitrogen (BUN), and creatinine levels. It also depressed the glomerular mesangial expansion. PIO down-regulated expression of AGEs, RAGE, and NF-κB, all of which further depressed NLRP3, caspase-1, IL-18, and IL-1β levels.

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-κB expression. These effects lead to a decline in NLRP3 levels and downstream secretion of inflammatory cytokines.