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MicroRNA-26a inhibits TGF-β-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy.
- Source :
-
Diabetologia [Diabetologia] 2015 Sep; Vol. 58 (9), pp. 2169-80. Date of Electronic Publication: 2015 Jun 11. - Publication Year :
- 2015
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Abstract
- Aims/hypothesis: The accumulation of extracellular matrix (ECM) is a characteristic of diabetic nephropathy, and is partially caused by profibrotic proteins TGF-β and connective tissue growth factor (CTGF). We aimed to identify microRNAs (miRNAs) targeting CTGF on podocytes in diabetic nephropathy.<br />Methods: We investigated miRNAs targeting CTGF on podocytes with miRNA array analysis and identified a candidate miRNA, miR-26a. Using overexpression and silencing of miR-26a in cultured podocytes, we examined changes of ECM and its host genes. We further investigated glomerular miR-26a expression in humans and in mouse models of diabetic nephropathy.<br />Results: miR-26a, which was downregulated by TGF-β1, was expressed in glomerular cells including podocytes and in tubules by in situ hybridisation. Glomerular miR-26a expression was downregulated by 70% in streptozotocin-induced diabetic mice. Transfection of miR-26a mimics in cultured human podocytes decreased the CTGF protein level by 50%, and directly inhibited CTGF expression in podocytes, as demonstrated by a reporter assay with the 3'-untranslated region of the CTGF gene. This effect was abolished by a mutant plasmid. miR-26a mimics also inhibited TGF-β1-induced collagen expression, SMAD-binding activity and expression of its host genes CTDSP2 and CTDSPL. Knockdown of CTDSP2 and CTDSPL increased collagen expression in TGF-β-stimulated podocytes, suggesting that host genes also regulate TGF-β/SMAD signalling. Finally, we observed a positive correlation between microdissected glomerular miR-26a expression levels and estimated GFR in patients with diabetic nephropathy.<br />Conclusions/interpretation: The downregulation of miR-26a is involved in the progression of diabetic nephropathy both in humans and in mice through enhanced TGF-β/CTGF signalling.
- Subjects :
- 3' Untranslated Regions
Animals
Base Sequence
Biopsy
Diabetes Mellitus, Experimental
Disease Progression
Down-Regulation
Female
Gene Expression Regulation
Gene Silencing
Glomerular Filtration Rate
Humans
Kidney Glomerulus metabolism
Male
Mice
MicroRNAs genetics
Microdissection
Middle Aged
Molecular Sequence Data
Nuclear Proteins metabolism
Phosphoprotein Phosphatases metabolism
Smad Proteins metabolism
Streptozocin
Tumor Suppressor Proteins metabolism
Connective Tissue Growth Factor metabolism
Diabetic Nephropathies metabolism
Extracellular Matrix metabolism
MicroRNAs metabolism
Podocytes metabolism
Transforming Growth Factor beta1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0428
- Volume :
- 58
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 26063197
- Full Text :
- https://doi.org/10.1007/s00125-015-3642-4