title: Downregulation of microRNA-30 facilitates podocyte injury and is prevented by glucocorticoids.
abstract: 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.
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Junnan
authors.initials: J
authors.lastname: Wu
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Fan
authors.forename: Caihong
authors.initials: C
authors.lastname: Zeng
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Chen
authors.forename: Weisong
authors.initials: W
authors.lastname: Qin
authors.forename: Changming
authors.initials: C
authors.lastname: Zhang
authors.forename: Wanfen
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.forename: Mingchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011692:Puromycin Aminonucleoside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; C556157:MIRN30 microRNA, rat; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D011692:Puromycin Aminonucleoside; D003907:Dexamethasone
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