Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members
| Autor: | Fan Yang, Xiaodong Zhu, Yue Lang, Mingchao Zhang, Yue Zhao, Zhihong Liu, Shaolin Shi, Junnan Wu, Xianguang Zhou, Feng Xu, Minlin Zhou, Shifeng Yun |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Angiotensin receptor Kidney Glomerulus chemistry.chemical_element Down-Regulation Calcium Pharmacology Losartan Podocyte TRPC6 03 medical and health sciences Downregulation and upregulation Drug Discovery medicine Animals Humans Calcium Signaling Genetics (clinical) Cells Cultured Podocytes Angiotensin II Calcineurin Mice Inbred C57BL MicroRNAs 030104 developmental biology medicine.anatomical_structure chemistry Hypertension cardiovascular system Molecular Medicine Kidney Diseases Angiotensin II Type 1 Receptor Blockers hormones hormone substitutes and hormone antagonists circulatory and respiratory physiology medicine.drug |
| Zdroj: | Journal of molecular medicine (Berlin, Germany). 95(8) |
| ISSN: | 1432-1440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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