title: Deletion of p66Shc longevity gene protects against experimental diabetic glomerulopathy by preventing diabetes-induced oxidative stress.
abstract: p66(Shc) 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 p66(Shc) deletion also protects from diabetic glomerulopathy by reducing oxidative stress. Streptozotocin-induced diabetic p66(Shc) 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 F2alpha levels and activation of nuclear factor kappaB (NF-kappaB) 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-kappaB than those from wild-type mice. These data support a role for oxidative stress in the pathogenesis of diabetic glomerulopathy and indicate that p66(Shc) is involved in the molecular mechanism(s) underlying diabetes-induced oxidative stress and oxidant-dependent renal injury.
authors.affiliation: Department of Clinical Sciences, La Sapienza University, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.forename: Lorena
authors.initials: L
authors.lastname: Amadio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Oddi
authors.forename: Carlo
authors.initials: C
authors.lastname: Ricci
authors.forename: Carlo
authors.initials: C
authors.lastname: Pesce
authors.forename: Francesco
authors.initials: F
authors.lastname: Pugliese
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Enrica
authors.initials: E
authors.lastname: Migliaccio
authors.forename: PierGiuseppe
authors.initials: P
authors.lastname: Pelicci
authors.forename: Carla
authors.initials: C
authors.lastname: Iacobini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000419:Albuminuria / Q000652:urine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003401:Creatine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015237:Dinoprost / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011507:Proteinuria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024141:Collagen Type IV; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015237:Dinoprost; D053148:Caspase 3; D005947:Glucose; D003401:Creatine