Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

S. Menini, C. Iacobini, C. Ricci, G. Oddi, C. Pesce, F. Pugliese, K. Block, H. E. Abboud, M. Giorgio, E. Migliaccio, P. G. Pelicci, G. Pugliese

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Aims/hypothesis: AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods: For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^\varepsilon - \left( {carboxymethyl} \right)\;\text{lysine} $$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results: Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation: These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production.

Original languageEnglish (US)
Pages (from-to)1997-2007
Number of pages11
JournalDiabetologia
Volume50
Issue number9
DOIs
StatePublished - Sep 2007

Fingerprint

Oxidants
Reactive Oxygen Species
Kidney
Knockout Mice
Wounds and Injuries
Genes
8-epi-prostaglandin F2alpha
Oxidative Stress
Up-Regulation
Dinoprost
Mesangial Cells
NADPH Oxidase
Sclerosis
Hyperlipidemias
Proteinuria
Hypertrophy
Lysine
Reperfusion
Extracellular Matrix
Albumins

Keywords

  • AGE receptors
  • AGEs
  • Apoptosis
  • Extracellular matrix
  • NAD(P)H oxidase
  • Nephropathy
  • NOX4
  • Nuclear factor κB
  • Oxidative stress
  • p66

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation. / Menini, S.; Iacobini, C.; Ricci, C.; Oddi, G.; Pesce, C.; Pugliese, F.; Block, K.; Abboud, H. E.; Giorgio, M.; Migliaccio, E.; Pelicci, P. G.; Pugliese, G.

In: Diabetologia, Vol. 50, No. 9, 09.2007, p. 1997-2007.

Research output: Contribution to journalArticle

Menini, S, Iacobini, C, Ricci, C, Oddi, G, Pesce, C, Pugliese, F, Block, K, Abboud, HE, Giorgio, M, Migliaccio, E, Pelicci, PG & Pugliese, G 2007, 'Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation', Diabetologia, vol. 50, no. 9, pp. 1997-2007. https://doi.org/10.1007/s00125-007-0728-7
Menini, S. ; Iacobini, C. ; Ricci, C. ; Oddi, G. ; Pesce, C. ; Pugliese, F. ; Block, K. ; Abboud, H. E. ; Giorgio, M. ; Migliaccio, E. ; Pelicci, P. G. ; Pugliese, G. / Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation. In: Diabetologia. 2007 ; Vol. 50, No. 9. pp. 1997-2007.
@article{8f3ce42dc4bc4d50be9a67e0e4143783,
title = "Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation",
abstract = "Aims/hypothesis: AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods: For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^\varepsilon - \left( {carboxymethyl} \right)\;\text{lysine} $$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results: Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F2α levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation: These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production.",
keywords = "AGE receptors, AGEs, Apoptosis, Extracellular matrix, NAD(P)H oxidase, Nephropathy, NOX4, Nuclear factor κB, Oxidative stress, p66",
author = "S. Menini and C. Iacobini and C. Ricci and G. Oddi and C. Pesce and F. Pugliese and K. Block and Abboud, {H. E.} and M. Giorgio and E. Migliaccio and Pelicci, {P. G.} and G. Pugliese",
year = "2007",
month = "9",
doi = "10.1007/s00125-007-0728-7",
language = "English (US)",
volume = "50",
pages = "1997--2007",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "9",

}

TY - JOUR

T1 - Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

AU - Menini, S.

AU - Iacobini, C.

AU - Ricci, C.

AU - Oddi, G.

AU - Pesce, C.

AU - Pugliese, F.

AU - Block, K.

AU - Abboud, H. E.

AU - Giorgio, M.

AU - Migliaccio, E.

AU - Pelicci, P. G.

AU - Pugliese, G.

PY - 2007/9

Y1 - 2007/9

N2 - Aims/hypothesis: AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods: For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^\varepsilon - \left( {carboxymethyl} \right)\;\text{lysine} $$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results: Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F2α levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation: These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production.

AB - Aims/hypothesis: AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods: For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^\varepsilon - \left( {carboxymethyl} \right)\;\text{lysine} $$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results: Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F2α levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation: These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production.

KW - AGE receptors

KW - AGEs

KW - Apoptosis

KW - Extracellular matrix

KW - NAD(P)H oxidase

KW - Nephropathy

KW - NOX4

KW - Nuclear factor κB

KW - Oxidative stress

KW - p66

UR - http://www.scopus.com/inward/record.url?scp=34547659642&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547659642&partnerID=8YFLogxK

U2 - 10.1007/s00125-007-0728-7

DO - 10.1007/s00125-007-0728-7

M3 - Article

C2 - 17611735

AN - SCOPUS:34547659642

VL - 50

SP - 1997

EP - 2007

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -