MicroRNA-26a inhibits TGF-ß-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy.
Diabetologia
; 58(9): 2169-80, 2015 Sep.
Article
en En
| MEDLINE
| ID: mdl-26063197
ABSTRACT
AIMS/HYPOTHESIS:
The accumulation of extracellular matrix (ECM) is a characteristic of diabetic nephropathy, and is partially caused by profibrotic proteins TGF-ß and connective tissue growth factor (CTGF). We aimed to identify microRNAs (miRNAs) targeting CTGF on podocytes in diabetic nephropathy.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.RESULTS:
miR-26a, which was downregulated by TGF-ß1, 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-ß1-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-ß-stimulated podocytes, suggesting that host genes also regulate TGF-ß/SMAD signalling. Finally, we observed a positive correlation between microdissected glomerular miR-26a expression levels and estimated GFR in patients with diabetic nephropathy. CONCLUSIONS/INTERPRETATION:
The downregulation of miR-26a is involved in the progression of diabetic nephropathy both in humans and in mice through enhanced TGF-ß/CTGF signalling.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
MicroARNs
/
Nefropatías Diabéticas
/
Podocitos
/
Matriz Extracelular
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Factor de Crecimiento Transformador beta1
/
Factor de Crecimiento del Tejido Conjuntivo
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Diabetologia
Año:
2015
Tipo del documento:
Article
País de afiliación:
Japón