Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2017-08, Vol.95 (8), p.887-898
• Main Authors: Zhao, Yue, Wu, Junnan, Zhang, Mingchao, Zhou, Minlin, Xu, Feng, Zhu, Xiaodong, Zhou, Xianguang, Lang, Yue, Yang, Fan, Yun, Shifeng, Shi, Shaolin, Liu, Zhihong
• Format: Article
• Language: English
• Subjects: Activation; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Biomedical and Life Sciences; Biomedicine; Calcineurin; Calcineurin - metabolism; Calcium; Calcium - metabolism; Calcium Signaling - drug effects; Calcium signalling; Cells, Cultured; Down-Regulation; Human Genetics; Humans; Hypertension - metabolism; Hypertension - pathology; Internal Medicine; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Losartan - pharmacology; Male; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Medicine; Original Article; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Rodents
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-017-1547-z

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. Key messages • 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.