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

Abstract

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. 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. 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- $${\text{F}}_{{2{\text{ $ \alpha $ }}}} $$ 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. 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.

DOI: 10.1007/s00125-007-0728-7

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@article{Menini2007AblationOT, title={Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation}, author={Stefano Menini and Carla Iacobini and Carlo Ricci and Giovanna Oddi and Carlo Pesce and Francesco Rocco Pugliese and Kenneth Block and Hanna Emily Abboud and Marco Giorgio and Enrica Migliaccio and Pier Giuseppe Pelicci and Giuseppe Pugliese}, journal={Diabetologia}, year={2007}, volume={50}, pages={1997-2007} }