title: Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy.
abstract: Glomerulosclerosis of any cause is characterized by loss of functional glomerular cells and deposition of excessive amounts of interstitial collagens including collagen I. We have previously reported that mesangial cell attachment to collagen I leads to upregulation of Hic-5 in vitro, which mediates mesangial cell apoptosis. Furthermore, glomerular Hic-5 expression was increased during the progression of experimental glomerulosclerosis. We hypothesized that reducing collagen I accumulation in glomerulosclerosis would in turn lower Hic-5 expression, reducing mesangial cell apoptosis, and thus maintaining glomerular integrity. We examined archive renal tissue from rats undergoing experimental diabetic glomerulosclerosis, treated with the transglutaminase-2 inhibitor NTU281. Untreated animals exhibited increased glomerular collagen I accumulation, associated with increased glomerular Hic-5 expression, apoptosis, and mesangial myofibroblast transdifferentiation characterized by α-smooth muscle actin (α-SMA) expression. NTU281 treatment reduced glomerular collagen I accumulation, Hic-5 and α-SMA expression, and apoptosis. Proteinurea and serum creatinine levels were significantly reduced in animals with reduced Hic-5 expression. In vitro studies of Hic-5 knockdown or overexpression show that mesangial cell apoptosis and expression of both α-SMA and collagen I are Hic-5 dependent. Together, these data suggest that there exists, in vitro and in vivo, a positive feedback loop whereby increased levels of collagen I lead to increased mesangial Hic-5 expression favoring not only increased apoptosis, but also mesangial myofibroblast transdifferentiation and increased collagen I expression. Prevention of collagen I accumulation interrupts this Hic-5-dependent positive feedback loop, preserving glomerular architecture, cellular phenotype, and function.
authors.affiliation: CRUK Clinical Research Centre, St James's University Hospital, Leeds, UK. j.n.a.hornigold@leeds.ac.uk
authors.forename: Nick
authors.initials: N
authors.lastname: Hornigold
authors.forename: Tim S
authors.initials: TS
authors.lastname: Johnson
authors.forename: Linghong
authors.initials: L
authors.lastname: Huang
authors.forename: John L
authors.initials: JL
authors.lastname: Haylor
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
authors.forename: Andrew
authors.initials: A
authors.lastname: Mooney
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D060588:LIM Domain Proteins / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000199:Actins; D024042:Collagen Type I; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C490352:Tgfb1i1 protein, rat; C000717609:Tgm2 protein, rat; D003404:Creatinine; D000091345:Protein Glutamine gamma Glutamyltransferase 2