IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1α

J Am Soc Nephrol. 2011 Aug;22(8):1475-85. doi: 10.1681/ASN.2010111154. Epub 2011 Jul 22.

Abstract

Increased expression of Induced-by-High-Glucose 1 (IHG-1) associates with tubulointerstitial fibrosis in diabetic nephropathy. IHG-1 amplifies TGF-β1 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 γ coactivator-1α (PGC-1α). Conversely, inhibition of IHG-1 expression decreased mitochondrial mass, downregulated mitochondrial proteins, and PGC-1α-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-1α 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-1α-dependent processes, potentially contributing to the pathogenesis of renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA, Mitochondrial / metabolism
  • Fibrosis / metabolism
  • Glucose / metabolism
  • HeLa Cells
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Hypoxia
  • Kidney Tubules / pathology
  • Male
  • Mitochondria / metabolism
  • Models, Biological
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Proteins / physiology*
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Rats, Wistar
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • DNA, Mitochondrial
  • Heat-Shock Proteins
  • IHG-1 protein, rat
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Proteins
  • RNA-Binding Proteins
  • THG1L protein, human
  • Transcription Factors
  • Glucose