Elevated ε-(γ-glutamyl)lysine in human diabetic nephropathy results from increased expression and cellular release of tissue transglutaminase

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

Research output: Contribution to journalArticle

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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 immunofl uorescence approach, with tTg and ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofl uorescent 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.

Original languageEnglish (US)
Pages (from-to)c108-c117
JournalNephron - Clinical Practice
Volume97
Issue number3
DOIs
StatePublished - Aug 27 2004

Fingerprint

Diabetic Nephropathies
Lysine
Kidney
Extracellular Matrix
Confocal Microscopy
Cicatrix
Cell Death
Biopsy
Transglutaminases
Streptozocin
transglutaminase 2
Type 2 Diabetes Mellitus
Chronic Kidney Failure
Atrophy
Epithelial Cells
Staining and Labeling
Enzymes
Proteins

Keywords

  • Chronic kidney failure
  • Diabetic nephropathy
  • Fibrosis
  • Scarring
  • Transglutaminase

ASJC Scopus subject areas

  • Nephrology

Cite this

Elevated ε-(γ-glutamyl)lysine in human diabetic nephropathy results from increased expression and cellular release of tissue transglutaminase. / El Nahas, A. M.; Abo-Zenah, H.; Skill, N. J.; Bex, S.; Wild, G.; Griffin, M.; Johnson, T. S.

In: Nephron - Clinical Practice, Vol. 97, No. 3, 27.08.2004, p. c108-c117.

Research output: Contribution to journalArticle

El Nahas, A. M. ; Abo-Zenah, H. ; Skill, N. J. ; Bex, S. ; Wild, G. ; Griffin, M. ; Johnson, T. S. / Elevated ε-(γ-glutamyl)lysine in human diabetic nephropathy results from increased expression and cellular release of tissue transglutaminase. In: Nephron - Clinical Practice. 2004 ; Vol. 97, No. 3. pp. c108-c117.
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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 immunofl uorescence approach, with tTg and ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofl uorescent 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.",
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AU - El Nahas, A. M.

AU - Abo-Zenah, H.

AU - Skill, N. J.

AU - Bex, S.

AU - Wild, G.

AU - Griffin, M.

AU - Johnson, T. S.

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N2 - 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 immunofl uorescence approach, with tTg and ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofl uorescent 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.

AB - 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 immunofl uorescence approach, with tTg and ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofl uorescent 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.

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KW - Diabetic nephropathy

KW - Fibrosis

KW - Scarring

KW - Transglutaminase

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