Anti-inflammatory role of microrna-146a in the pathogenesis of diabetic nephropathy

Abstract

Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role ofmicroRNA-146a (miR-146a), a known anti-inflammatorymicroRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a2/2 mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a2/2 than in the kidneys ofwild-typemice. Notably,miR-146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically,miR-146a deficiency during diabetes led to increased expression ofM1 activationmarkers and suppression ofM2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1b and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a2/2 mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism inmiR-146a2/2 mice leads to acceleratedDN. Taken together, these results identifymiR-146a as a novel anti-inflammatory noncoding RNA modulator of DN.