Date Published: July 14, 2017
Publisher: Public Library of Science
Author(s): Yao Wang, Bo Yu, Li Wang, Ming Yang, Zhiyin Xia, Wei Wei, Fengyu Zhang, Xiaochen Yuan, David M. Ojcius.
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.
The prevalence of diabetes mellitus has been growing worldwide, but available treatment for this disease remains limited. Despite the decline in mortality from macrovascular diabetic complications, diabetic nephropathy (DN) is still a leading cause of end-stage renal disease (ESRD), and the number is still rising. It has been reported that once nephropathy develops in patients with diabetes, approximately 40% inevitably progress to ESRD .
In the current study, we found that 8-week treatment with PIO significantly ameliorated the diabetes-induced increases in serum glucose, cholesterol, BUN, and creatinine in apoE (-/-) mice. However, PIO exhibited no effect on the diabetes-induced increases in absolute KW and KW/BW ratios. In PIO-treated apoE (-/-) and diabetic apoE (-/-) mice, activation of NF-κB and the AGE/RAGE axis were partially suppressed. PIO significantly attenuated the diabetes-induced activation of the NLRP3 inflammasomes and their downstream effectors, including caspase-1, IL-1β, and IL-18. In light of these findings, PIO could delay the progression of DN in mice with type 1 diabetes mellitus.
In conclusion, hyperglycemia and hyperlipidemia can lead to the activation of NLRP3 inflammasomes, and their downstream molecules, including caspase-1, IL-1β, and IL-18, in the glomerular mesangium. PIO treatment can inhibit the secretion of inflammatory cytokines through mechanisms including suppression of the AGE/RAGE signaling pathway and local ROS release, as well as lowering NF-κB levels, both of which attenuate NLRP3 infalmmasome activation and reduce diabetic renal injury. Our findings show that PIO, a PPAR-γ agonist, ameliorate DN and this is associated with downregulation of the NLRP3 inflammasome, potentially providing a new underlying mechanism responsible for the beneficial effect of PIO for DN.