Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy
Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy
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DOI：
10.1681/asn.2015010111
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发表时间：
2016-08-01
影响因子：
13.6
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
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作者：
Bhatt, Kirti;Lanting, Linda L.;Natarajan, Rama
炎症在糖尿病并发症（包括糖尿病肾病（DN））的发病机制中具有关键作用。microRNA最近成为DN的重要调节因子。然而，微小RNA在DN期间炎症调节中的作用知之甚少。在这里，我们研究了microRNA-146 a（miR-146 a），一种已知的抗炎microRNA，在DN发病机制中的体内作用。在链脲佐菌素诱导的糖尿病模型中，miR-146 a（-/-）小鼠显示相对于对照野生型小鼠中的相应水平显著加重的蛋白尿、肾巨噬细胞浸润、肾小球肥大和纤维化。糖尿病诱导的促炎基因和促纤维化基因的上调在miR-146 a（-/-）小鼠的肾脏中显著高于野生型小鼠的肾脏。值得注意的是，在糖尿病野生型小鼠的腹膜和肾内巨噬细胞中，miR 146 a表达增加。从机制上讲，糖尿病期间miR-146 a缺乏导致巨噬细胞中M1活化标志物表达增加和M2标志物抑制。伴随着促炎细胞因子如IL-1 β和IL-18的表达增加，糖尿病miR-146 a（-/-）小鼠的巨噬细胞中炎性小体活化的标志物也增加。这些研究表明，在早期DN中，miR-146 a上调通过下调靶炎症相关基因发挥保护作用，从而抑制促炎症和炎性体基因活化。在miR-146 a（-/-）小鼠中这种保护机制的丧失导致加速的DN。综上所述，这些结果将miR-146 a鉴定为DN的新型抗炎非编码RNA调节剂。
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 of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a(-/-) 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-146a(-/-) than in the kidneys of wild-type mice. Notably, miR146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1 beta and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a(-/-) 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 in miR-146a(-/-) mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN.