MicroRNA-26a inhibits TGF-β-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy

Kenichi Koga, Hideki Yokoi, Kiyoshi Mori, Masato Kasahara, Takashige Kuwabara, Hirotaka Imamaki, Akira Ishii, Keita P Mori, Yukiko Kato, Shoko Ohno, Naohiro Toda, Moin A Saleem, Akira Sugawara, Kazuwa Nakao, Motoko Yanagita, Masashi Mukoyama

Research output: Contribution to journalArticle (Academic Journal)

62 Citations (Scopus)

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.

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-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.

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.

Original languageEnglish
Pages (from-to)2169-80
Number of pages12
JournalDiabetologia
Volume58
Issue number9
DOIs
Publication statusPublished - Sep 2015

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