Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
J Am Soc Nephrol. 2014 Jan;25(1):92-104. doi: 10.1681/ASN.2012111101. Epub 2013 Sep 12.
MicroRNAs (miRNAs) are essential for podocyte homeostasis, and the miR-30 family may be responsible for this action. However, the exact roles and clinical relevance of miR-30s remain unknown. In this study, we examined the expression of the miR-30 family in the podocytes of patients with FSGS and found that all members are downregulated. Treating cultured human podocytes with TGF-β, LPS, or puromycin aminonucleoside (PAN) also downregulated the miR-30 family. Podocyte cytoskeletal damage and apoptosis caused by treatment with TGF-β or PAN were ameliorated by exogenous miR-30 expression and aggravated by miR-30 knockdown. Moreover, we found that miR-30s exert their protective roles by direct inhibition of Notch1 and p53, which mediate podocyte injury. In rats, treatment with PAN substantially downregulated podocyte miR-30s and induced proteinuria and podocyte injury; however, transfer of exogenous miR-30a to podocytes of PAN-treated rats ameliorated proteinuria and podocyte injury and reduced Notch1 activation. Finally, we demonstrated that glucocorticoid treatment maintains miR-30 expression in cultured podocytes treated with TGF-β, LPS, or PAN and in the podocytes of PAN-treated rats. Glucocorticoid-sustained miR-30 expression associated with reduced Notch1 activation and alleviated podocyte damage. Taken together, these findings demonstrate that miR-30s protect podocytes by targeting Notch1 and p53 and that the loss of miR-30s facilitates podocyte injury. In addition, sustained miR-30 expression may be a novel mechanism underlying the therapeutic effectiveness of glucocorticoids in treating podocytopathy.
微小 RNA（miRNAs）对足细胞的稳态至关重要，miR-30 家族可能负责这一作用。然而，miR-30s 的确切作用和临床相关性尚不清楚。在这项研究中，我们检查了 FSGS 患者足细胞中 miR-30 家族的表达，发现所有成员均下调。用 TGF-β、LPS 或嘌呤霉素氨基核苷（PAN）处理培养的人足细胞也下调了 miR-30 家族。外源性 miR-30 表达可减轻 TGF-β 或 PAN 引起的足细胞骨架损伤和凋亡，并加重 miR-30 敲低引起的损伤。此外，我们发现 miR-30s 通过直接抑制 Notch1 和 p53 发挥其保护作用，Notch1 和 p53 介导足细胞损伤。在大鼠中，PAN 处理大大地下调了足细胞 miR-30s，导致蛋白尿和足细胞损伤；然而，外源性 miR-30a 转染到 PAN 处理的大鼠足细胞中可改善蛋白尿和足细胞损伤，并减少 Notch1 激活。最后，我们证明糖皮质激素治疗可维持 TGF-β、LPS 或 PAN 处理的培养足细胞以及 PAN 处理的大鼠足细胞中 miR-30 的表达，并与减少 Notch1 激活和减轻足细胞损伤相关。综上所述，这些发现表明 miR-30s 通过靶向 Notch1 和 p53 保护足细胞，而 miR-30s 的缺失促进了足细胞损伤。此外，miR-30 的持续表达可能是糖皮质激素治疗足细胞病变的治疗效果的一种新机制。
