miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin
| Autor: | Joan C. Krepinsky, Dan Zhang, Ivan Zhang, Asfia Soomro, Bo Gao, Juehua He, Melissa E. MacDonald, Neel Mehta, Renzhong Li |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Follistatin Locked nucleic acid Science Glomerular Mesangial Cell medicine.medical_treatment Caveolin 1 Glomerular diseases Kidney Article Transforming Growth Factor beta1 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Renal fibrosis In vivo Chronic kidney disease Caveolae microRNA medicine Animals Humans Renal Insufficiency Chronic Mice Knockout Multidisciplinary biology Fibrosis 3. Good health MicroRNAs 030104 developmental biology Cytokine Gene Expression Regulation 030220 oncology & carcinogenesis Mesangial Cells miRNAs biology.protein Cancer research Medicine human activities |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3′UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFβ1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFβ1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFβ1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD. |
| Databáze: | OpenAIRE |
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