Deletion of p66Shc Longevity Gene Protects Against Experimental Diabetic Glomerulopathy by Preventing Diabetes-Induced Oxidative Stress

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 F2␣ levels and activation of nuclear factor B (NF-B) 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-B 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.

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

“…Interestingly, the p66 Shc promoter is subject to epigenetic modifications (14), and glucose-induced hypomethylation and hyperacetylation of the p66 Shc promoter results in high levels of p66 Shc expression and ROS generation in endothelial cells (15). In agreement with these data, p66 Shc -deficient mice are protected against diabetic nephropathy (16,17). However, the mechanisms that control p66 Shc expression in diabetic nephropathy remain unknown.…”

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

“…Recently, p66 Shc knockout mice were found to exhibit protection from hyperglycaemiainduced microvascular disease [19] and from development of diabetic autonomic neuropathy [20]. Levels of p66 Shc mRNA and p66 Shc protein were found to be increased in the kidney cortex of diabetic mice [19] and in circulating leucocytes from diabetic patients [21], suggesting that p66 Shc could 'sense' the impaired metabolic milieu in diabetes and promote cellular dysfunction. In support of this concept, the p66 Shc protein was found to act as a downstream effector of the tumour suppressor p53 gene in oxidative stress-induced apoptosis [18,22], and a p53 response element in the gene promoter of p66 Shc has also been identified [23].…”

“…p66 Shc signalling is strictly dependent upon phosphorylation of Ser 36 in the protein CH2 domain, triggered by cell exposure to oxidative stress-inducing agents [18]. Recently, p66 Shc knockout mice were found to exhibit protection from hyperglycaemiainduced microvascular disease [19] and from development of diabetic autonomic neuropathy [20]. Levels of p66 Shc mRNA and p66 Shc protein were found to be increased in the kidney cortex of diabetic mice [19] and in circulating leucocytes from diabetic patients [21], suggesting that p66 Shc could 'sense' the impaired metabolic milieu in diabetes and promote cellular dysfunction.…”

Inside Lab Invest

“…Finally, high glucose does not increase intracellular ROS levels in the mesangial cells of diabetic p66Shc-deficient mice. 8 Most recently, glomerular cell apoptosis has been recognized as an early event in the nephropathy of murine type-1 and 2 DM models in vivo, with increasing cell death levels parallelling the inception and progression of urinary albumin excretion. 9 Another recent acquisition is that podocytes have been identified as the main glomerular cell type that undergoes apoptosis 8,9 in response to glucose-induced ROS production.…”

“…8 Most recently, glomerular cell apoptosis has been recognized as an early event in the nephropathy of murine type-1 and 2 DM models in vivo, with increasing cell death levels parallelling the inception and progression of urinary albumin excretion. 9 Another recent acquisition is that podocytes have been identified as the main glomerular cell type that undergoes apoptosis 8,9 in response to glucose-induced ROS production. 9 In summary, further studies should be undertaken to highlight the pathways of the proapoptotic effect of high glucose on glomerular cells.…”