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

Madeline Murphy^*, Neil G. Docherty^*, Brenda Griffin^*, Jillian Howlin^*, Emmett McArdle^*, Ruth McMahon^*, Holger Schmid, Matthias Kretzler, Alejandra Droguett, Sergio Mezzano, Hugh R. Brady^*, Fiona Furlong^*, Catherine Godson^* and Finian Martin^*

^* UCD Diabetes Research Centre, Conway Institute, Schools of Medicine and Medical Science and Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland; Medizinische Poliklinik, Ludwig-Maximilians-University of Munich, Munich, Germany; and Department of Nephrology, Universidad Austral, Valdivia, Chile

Correspondence: Dr. Madeline Murphy, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. Phone: +353-1-7166818; Fax: +353-1-7166713; E-mail: madeline.murphy{at}ucd.ie

Received for publication October 8, 2007. Accepted for publication March 14, 2008.

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.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673