期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 22, 期 8, 页码 1475-1485出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2010111154
关键词
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资金
- Science Foundation Ireland
- Health Research Board
- Government of Ireland
Increased expression of Induced-by-High-Glucose 1 (IHG-1) associates with tubulointerstitial fibrosis in diabetic nephropathy. IHG-1 amplifies TGF-beta 1 signaling, but the functions of this highly-conserved protein are not well understood. IHG-1 contains a putative mitochondrial-localization domain, and here we report that IHG-1 is specifically localized to mitochondria. IHG-1 overexpression increased mitochondrial mass and stabilized peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Conversely, inhibition of IHG-1 expression decreased mitochondrial mass, downregulated mitochondrial proteins, and PGC-1 alpha-regulated transcription factors, including nuclear respiratory factor 1 and mitochondrial transcription factor A (TFAM), and reduced activity of the TFAM promoter. In the unilateral ureteral obstruction model, we observed higher PGC-1 alpha protein expression and IHG-1 levels with fibrosis. In a gene-expression database, we noted that renal biopsies of human diabetic nephropathy demonstrated higher expression of genes encoding key mitochondrial proteins, including cytochrome c and manganese superoxide dismutase, compared with control biopsies. In summary, these data suggest that IHG-1 increases mitochondrial biogenesis by promoting PGC-1 alpha-dependent processes, potentially contributing to the pathogenesis of renal fibrosis.
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