MicroRNA-29b Inhibits Diabetic Nephropathy in db/db Mice
MicroRNA-29b Inhibits Diabetic Nephropathy in db/db Mice
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DOI：
10.1038/mt.2013.235
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发表时间：
2014-04-01
影响因子：
12.4
通讯作者：
Lan, Hui Y.
中科院分区：
文献类型：
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作者：
Chen, Hai-Yong;Zhong, Xiang;Lan, Hui Y.
炎症及其导致的纤维化是糖尿病肾病（DN）的两个主要特征，但针对这些过程的DN靶向治疗仍然无效。我们在此报告，miR-29 b是一种新型治疗剂，能够抑制db/db小鼠2型糖尿病的进行性肾脏炎症和纤维化。在糖尿病条件下，miR-29 b响应于晚期糖基化终末（AGE）产物而大幅下调，这与通过转化生长因子-β（TGF-β）/Smad 3依赖性机制上调系膜细胞中的胶原基质相关。过表达miR-29 b可逆转这些病理变化，但敲低miR-29 b可增强这些病理变化。类似地，肾脏miR-29 b的丢失与进行性糖尿病肾损伤相关，包括微量白蛋白尿、肾纤维化和炎症。通过基于超声的基因治疗恢复的肾脏miR-29 b能够减轻糖尿病肾病。进一步的研究表明，抑制Sp1表达、TGF-β/Smad 3依赖性肾纤维化、NF-κ B驱动的肾脏炎症和T-bet/Th 1介导的免疫应答可能是与miR-29 b治疗db/db小鼠相关的机制。结论：miR-29 b可能在糖尿病肾病中发挥保护作用，并可能对糖尿病肾病并发症具有治疗潜力。
Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-beta (TGF-beta)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-beta/Smad3-dependent renal fibrosis, NF-kappa B-driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication.