Chen Hai-Yong, Zhong Xiang, Huang Xiao R, Meng Xiao-Ming, You Yongke, Chung Arthur Ck, Lan Hui Y
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
1] Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] CUHK Shenzhen Research Institute, Shenzhen, The Chinese University of Hong Kong, Hong Kong, China.
Mol Ther. 2014 Apr;22(4):842-53. doi: 10.1038/mt.2013.235. Epub 2013 Dec 6.
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-β (TGF-β)/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-β/Smad3-dependent renal fibrosis, NF-κB-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.
炎症及其引发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-29b是一种新型治疗剂，能够抑制db/db小鼠2型糖尿病中的进行性肾脏炎症和纤维化。在糖尿病条件下，miR-29b在晚期糖基化终末（AGE）产物的作用下大量下调，这与通过转化生长因子-β（TGF-β）/Smad3依赖性机制上调系膜细胞中的胶原基质有关。这些病理变化通过过表达miR-29b得以逆转，但通过敲低miR-29b而增强。同样，肾脏miR-29b的缺失与进行性糖尿病肾损伤有关，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肾脏miR-29b能够减轻糖尿病肾病。进一步的研究表明，抑制Sp1表达、TGF-β/Smad3依赖性肾纤维化、NF-κB驱动的肾炎症以及T-bet/Th1介导的免疫反应可能是与db/db小鼠中miR-29b治疗相关的机制。总之，miR-29b可能在糖尿病肾病中发挥保护作用，并且可能对糖尿病肾脏并发症具有治疗潜力。
