IHG-1 Amplifies TGF-β1 Signaling and Is Increased in Renal Fibrosis

• Published in: Journal of the American Society of Nephrology Vol. 19; no. 9; pp. 1672 - 1680
• Main Authors: MURPHY, Madeline, DOCHERTY, Neil G, BRADY, Hugh R, FURLONG, Fiona, GODSON, Catherine, MARTIN, Finian, GRIFFIN, Brenda, HOWLIN, Jillian, MCARDLE, Emmett, MCMAHON, Ruth, SCHMID, Holger, KRETZLER, Matthias, DROGUETT, Alejandra, MEZZANO, Sergio
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.09.2008; American Society of Nephrology
• Subjects: Basic Research; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Urinary system involvement in other diseases. Miscellaneous; Endocrinopathy; Kidney disease; Human; Nephrology; Urinary system disease; Renal fibrosis; Pathogenesis; Diabetes mellitus; Urology; Signal transduction; Concomitant disease; Nephropathy; Gene; Diabetic nephropathy; Transforming growth factor β1
• DOI: 10.1681/asn.2007101080
• ISSN: 1046-6673

Induced in high glucose-1 (IHG-1) is an evolutionarily conserved gene transcript upregulated by high extracellular glucose concentrations, but its function is unknown. Here, it is reported that the abundance of IHG-1 mRNA is nearly 10-fold higher in microdissected, tubule-rich renal biopsies from patients with diabetic nephropathy compared with control subjects. In the diabetic nephropathy specimens, in situ hybridization localized IHG-1 to tubular epithelial cells along with TGF-β1 and activated Smad3, suggesting a possible role in the development of tubulointerstitial fibrosis. Supporting this possibility, IHG-1 mRNA and protein expression also increased with unilateral ureteral obstruction. In the HK-2 proximal tubule cell line, overexpression of IHG-1 increased TGF-β1–stimulated expression of connective tissue growth factor and fibronectin. IHG-1 was found to amplify TGF-β1–mediated transcriptional activity by increasing and prolonging phosphorylation of Smad3. Conversely, inhibition of endogenous IHG-1 with small interference RNA suppressed transcriptional responses to TGF-β1. In summary, IHG-1, which increases in diabetic nephropathy, may enhance the actions of TGF-β1 and contribute to the development of tubulointerstitial fibrosis.