Zhao Yue, Wu Junnan, Zhang Mingchao, Zhou Minlin, Xu Feng, Zhu Xiaodong, Zhou Xianguang, Lang Yue, Yang Fan, Yun Shifeng, Shi Shaolin, Liu Zhihong
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China.
Comparative Medicine Department, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China.
J Mol Med (Berl). 2017 Aug;95(8):887-898. doi: 10.1007/s00109-017-1547-z. Epub 2017 May 24.
Angiotensin II (AngII) is capable of inducing calcium/calcineurin signaling and podocyte injury; however, the precise underlying mechanism is not well understood. Because we have previously demonstrated that microRNA-30s (miR-30s) inhibit calcium/calcineurin signaling in podocytes, we hypothesize that AngII may induce podocyte injury by downregulating miR-30s and thereby activating calcium/calcineurin signaling. To test this hypothesis, we used an AngII-induced podocyte injury mouse model. The mice were treated with AngII via infusion for 28 days, which resulted in hypertension, albuminuria, and glomerular damage. AngII treatment also resulted in a significant reduction of miR-30s and upregulation of calcium/calcineurin signaling components, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, which are the known targets of miR-30s in podocytes. The delivery of miR-30a-expressing lentivirus to the podocytes on day 14 of the infusion ameliorated the AngII-induced podocyte and glomerular injury and attenuated the upregulation of the calcium/calcineurin signaling components. Similarly, treatment with losartan, which is an AngII receptor blocker, also prevented AngII-induced podocyte injury and calcium/calcineurin signaling activation. Notably, losartan was found to sustain miR-30 levels during AngII treatment both in vivo and in vitro. In conclusion, the effect of AngII on podocytes is in part mediated by miR-30s through calcium/calcineurin signaling, a novel mechanism underlying AngII-induced podocyte injury.
• AngII infusion resulted in downregulation of miR-30s in podocytes. • Exogenous miR-30a delivery mitigated the glomerular and podocyte injuries induced by AngII. • Both miR-30a and losartan prevented AngII-induced activation of calcium-calcineurin signaling.
血管紧张素II（AngII）能够诱导钙/钙调神经磷酸酶信号传导和足细胞损伤；然而，其确切的潜在机制尚不完全清楚。由于我们之前已经证明微小RNA-30（miR-30）抑制足细胞中的钙/钙调神经磷酸酶信号传导，我们推测AngII可能通过下调miR-30从而激活钙/钙调神经磷酸酶信号传导来诱导足细胞损伤。为了验证这一假设，我们使用了AngII诱导的足细胞损伤小鼠模型。通过输注对小鼠进行AngII处理28天，这导致了高血压、蛋白尿和肾小球损伤。AngII处理还导致miR-30显著减少以及钙/钙调神经磷酸酶信号传导成分上调，包括瞬时受体电位通道蛋白6（TRPC6）、蛋白磷酸酶3催化亚基α（PPP3CA）、蛋白磷酸酶3催化亚基β（PPP3CB）、蛋白磷酸酶3调节亚基Bα（PPP3R1）和活化T细胞核因子3（NFATC3），这些都是足细胞中miR-30的已知靶标。在输注第14天向足细胞递送表达miR-30a的慢病毒可改善AngII诱导的足细胞和肾小球损伤，并减弱钙/钙调神经磷酸酶信号传导成分的上调。同样，使用血管紧张素II受体阻滞剂氯沙坦进行治疗也可预防AngII诱导的足细胞损伤和钙/钙调神经磷酸酶信号传导激活。值得注意的是，发现氯沙坦在体内和体外的AngII处理过程中均能维持miR-30水平。总之，AngII对足细胞的作用部分是由miR-30通过钙/钙调神经磷酸酶信号传导介导的，这是AngII诱导足细胞损伤的一种新机制。
• AngII输注导致足细胞中miR-30下调。
• 外源性递送miR-30a减轻了AngII诱导的肾小球和足细胞损伤。
• miR-30a和氯沙坦均可预防AngII诱导的钙-钙调神经磷酸酶信号传导激活。
