Madeline Murphy1, Fionnuala Hickey, Catherine Godson. 1. UCD Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
Abstract
PURPOSE OF REVIEW: This review focuses on the role of the mitochondrial protein induced in high glucose 1 (IHG-1) in kidney fibrosis. RECENT FINDINGS: Diabetic nephropathy is the most common cause of end-stage renal disease. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator of fibrosis and diabetic nephropathy. IHG-1 was identified in a screen for genes differentially expressed in renal cells exposed to high glucose. Here we review the biology of this novel functionally uncharacterized gene transcript. Data from human biopsy material and experimental models indicate increased expression of IHG-1 is a critical component of fibrogenesis as it amplifies TGF-β1 signalling. IHG-1 is expressed in mitochondria, stabilizes PGC-1α protein and increases mitochondrial biogenesis. Recently the crystal structure of IHG-1 has been determined revealing structural homology with canonical 5'→ 3' DNA polymerases and adenylyl/guanylyl cyclases, whereas the closely related yeast homologue has been shown to function as a tRNA(HIS) guanyltransferase. SUMMARY: IHG-1 is a transcript up-regulated in renal cells exposed to high glucose, in animal models of renal fibrosis and in human diabetic nephropathy. IHG-1 encodes a mitochondrial protein that amplifies fibrotic responses to TGF-β1 and promotes mitochondrial biogenesis. Investigation of the functional significance of the highly conserved domains of IHG-1 may lead to new therapeutic strategies.
PURPOSE OF REVIEW: This review focuses on the role of the mitochondrial protein induced in high glucose 1 (IHG-1) in kidney fibrosis. RECENT FINDINGS:Diabetic nephropathy is the most common cause of end-stage renal disease. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator of fibrosis and diabetic nephropathy. IHG-1 was identified in a screen for genes differentially expressed in renal cells exposed to high glucose. Here we review the biology of this novel functionally uncharacterized gene transcript. Data from human biopsy material and experimental models indicate increased expression of IHG-1 is a critical component of fibrogenesis as it amplifies TGF-β1 signalling. IHG-1 is expressed in mitochondria, stabilizes PGC-1α protein and increases mitochondrial biogenesis. Recently the crystal structure of IHG-1 has been determined revealing structural homology with canonical 5'→ 3' DNA polymerases and adenylyl/guanylyl cyclases, whereas the closely related yeast homologue has been shown to function as a tRNA(HIS) guanyltransferase. SUMMARY: IHG-1 is a transcript up-regulated in renal cells exposed to high glucose, in animal models of renal fibrosis and in humandiabetic nephropathy. IHG-1 encodes a mitochondrial protein that amplifies fibrotic responses to TGF-β1 and promotes mitochondrial biogenesis. Investigation of the functional significance of the highly conserved domains of IHG-1 may lead to new therapeutic strategies.