UCD Diabetes Research Centre, UCD Conway Institute, Ireland.
J Am Soc Nephrol. 2011 Aug;22(8):1475-85. doi: 10.1681/ASN.2010111154. Epub 2011 Jul 22.
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.
高糖诱导蛋白 1（IHG-1）的表达增加与糖尿病肾病的肾小管间质纤维化有关。IHG-1 放大 TGF-β1 信号，但这种高度保守的蛋白质的功能尚未得到很好的理解。IHG-1 包含一个假定的线粒体定位结构域，在这里我们报告 IHG-1 特异性定位于线粒体。IHG-1 的过表达增加了线粒体的质量并稳定了过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）。相反，抑制 IHG-1 的表达降低了线粒体的质量，下调了线粒体蛋白和 PGC-1α 调节的转录因子，包括核呼吸因子 1 和线粒体转录因子 A（TFAM），并降低了 TFAM 启动子的活性。在单侧输尿管梗阻模型中，我们观察到纤维化时 PGC-1α 蛋白表达和 IHG-1 水平升高。在基因表达数据库中，我们注意到与对照活检相比，人类糖尿病肾病的肾活检显示编码关键线粒体蛋白的基因表达更高，包括细胞色素 c 和锰超氧化物歧化酶。总之，这些数据表明，IHG-1 通过促进 PGC-1α 依赖性过程增加线粒体生物发生，可能有助于肾脏纤维化的发病机制。
