Nephron Clinical Practice

Original Paper

Elevated ε-(γ-Glutamyl)lysine in Human Diabetic Nephropathy Results from Increased Expression and Cellular Release of Tissue Transglutaminase

El Nahas A.M.a · Abo-Zenah H.a · Skill N.J.a,c · Bex S.b · Wild G.b · Griffin M.c · Johnson T.S.a

Author affiliations

aSheffield Kidney Institute and bDepartment of Immunology, Sheffield Teaching Hospitals Trust, Sheffield, and cDepartment of Life Sciences, Nottingham Trent University, Nottingham, UK

Keywords: FibrosisScarringChronic kidney failureTransglutaminaseDiabetic nephropathy

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Nephron Clin Pract 2004;97:c108–c117
https://doi.org/10.1159/000078639

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: November 27, 2003
Accepted: March 18, 2004
Published online: November 17, 2004
Issue release date: July 2004

Number of Print Pages: 1
Number of Figures: 6
Number of Tables: 1


eISSN: 1660-2110 (Online)

For additional information: https://www.karger.com/NEC

Abstract

Introduction: Diabetic nephropathy (DN) is the leading cause of chronic kidney failure, however the mechanisms underlying the characteristic expansion of the extracellular matrix (ECM) in diabetic kidneys remain controversial and unclear. In non-diabetic kidney scarring the protein crosslinking enzyme tissue transglutaminase (tTg) has been implicated in this process by the formation of increased Ε-(γ-glutamyl)lysine bonds between ECM components in both experimental and human disease. Studies in db+/db+ diabetic mice and in streptozotocin-treated rats have suggested a similar mechanism, although the relevance of this to human disease has not been addressed. Methods: We have undertaken a retrospective analysis of renal biopsies from 16 DN patients with type 2 diabetes mellitus using an immunohistochemical and immunofluorescence approach, with tTg and Ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofluorescent analysis of human biopsies (confocal microscopy) showed increases in levels of tTg (+1,266%, p < 0.001) and Ε-(γ-glutamyl)lysine (+486%, p < 0.001) in kidneys with DN compared to normal. Changes were predominantly in the extracellular periglomerular and peritubular areas. tTg staining correlated with Ε-(γ-glutamyl)lysine (r = 0.615, p < 0.01) and renal scarring (Masson’s trichrome, r = 0.728, p < 0.001). Significant changes in Ε-(γ-glutamyl)lysine were also noted intracellularly in some (≤5%) tubular epithelial cells. This is consistent with cells undergoing a novel transglutaminase-mediated cell death process in response to Ca2+ influx and subsequent activation of intracellular tTg. Conclusion: Changes in tTg and Ε-(γ-glutamyl)lysine occur in human DN. Cellular export of tTg may therefore be a factor in the perpetuation of DN by crosslinking and stabilisation of the ECM, while intracellular activation may lead to cell death contributing towards tubular atrophy.

© 2004 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: November 27, 2003
Accepted: March 18, 2004
Published online: November 17, 2004
Issue release date: July 2004

Number of Print Pages: 1
Number of Figures: 6
Number of Tables: 1


eISSN: 1660-2110 (Online)

For additional information: https://www.karger.com/NEC

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