Deletion of p66Shc longevity gene protects against experimental diabetic glomerulopathy by preventing diabetes-induced oxidative stress

Stefano Menini, Lorena Amadio, Giovanna Oddi, Carlo Ricci, Carlo Pesce, Francesco Pugliese, Marco Giorgio, Enrica Migliaccio, PierGiuseppe Pelicci, Carla Iacobini, Giuseppe Pugliese

Research output: Contribution to journalArticlepeer-review

Abstract

p66Shc regulates both steady-state and environmental stress-dependent reactive oxygen species (ROS) generation. Its deletion was shown to confer resistance to oxidative stress and protect mice from aging-associated vascular disease. This study was aimed at verifying the hypothesis that p66Shc deletion also protects from diabetic glomerulopathy by reducing oxidative stress. Streptozotocin-induced diabetic p66Shc knockout (KO) mice showed less marked changes in renal function and structure, as indicated by the significantly lower levels of proteinuria, albuminuria, glomerular sclerosis index, and glomerular and mesangial areas. Glomerular content of fibronectin and collagen IV was also lower in diabetic KO versus wild-type mice, whereas apoptosis was detected only in diabetic wild-type mice. Serum and renal tissue advanced glycation end products and plasma isoprostane 8-epi-prostaglandin F2α levels and activation of nuclear factor κB (NF-κB) were also lower in diabetic KO than in wild-type mice. Mesangial cells from KO mice grown under high-glucose conditions showed lower cell death rate, matrix production, ROS levels, and activation of NF-κB than those from wild-type mice. These data support a role for oxidative stress in the pathogenesis of diabetic glomerulopathy and indicate that p66Shc is involved in the molecular mechanism(s) underlying diabetes-induced oxidative stress and oxidant-dependent renal injury.

Original languageEnglish
Pages (from-to)1642-1650
Number of pages9
JournalDiabetes
Volume55
Issue number6
DOIs
Publication statusPublished - 2006

Keywords

  • Age, advanced glycation end product
  • CM-HDCFDA, 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate
  • CML, carboxymethyllysine
  • ECM, extracellular matrix
  • ELISA, enzyme-linked immunosorbent assay

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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