Overexpression of Cu2+/Zn2+ Superoxide Dismutase Protects Against Early Diabetic Glomerular Injury in Transgenic Mice

Craven, Patricia A.; Melhem, Mona F.; Phillips, Stephen L.; DeRubertis, Frederick R.

doi:10.2337/diabetes.50.9.2114

Cited by 143 publications

(113 citation statements)

References 61 publications

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“…Conversely, ROS-independent effects do not appear to contribute significantly to AGE-induced renal tissue injury. This observation is in agreement with previous studies, indicating that interventions aimed at reducing oxidative stress are effective in preventing different types of experimental renal disease [43][44][45][46] and that amelioration of diabetic and nondiabetic renal and cardiovascular disease observed in the p66 Shc KO mouse model is associated with reduction of oxidative stress [34][35][36][37][38].…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2007

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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 p66 Shc , 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 " À carboxymethyl ð Þ 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 2! 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 p66 Shc 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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2007

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“…14 C]inulin given by osmotic minipumps (Durect, Cupertino, CA) implanted subcutaneously, as previously reported (5,11). C IN and fractional clearance of albumin (FC Alb ) were calculated as previously described (5,11).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we demonstrated that transgenic mice that overexpress human cytoplasmic Cu 2ϩ / Zn 2ϩ superoxide dismutase (SOD)-1 are protected from early diabetic renal injury compared with their nontransgenic diabetic littermates in a model of streptozotocin (STZ)-induced type 1 diabetes (11). These observations provided the first in vivo evidence for the involvement of superoxide in the pathogenesis of diabetic nephropathy.…”

mentioning

confidence: 97%

“…Thus, increases in ROS in the diabetic environment may alter several redox-sensitive genes and/or cellular signaling pathways (1,2). With respect to diabetic nephropathy, studies in cultured mesangial cells support a role for increased superoxide production in signaling increases in matrix protein synthesis induced by either high ambient glucose concentrations or angiotensin-II (11,12), two factors strongly linked to renal injury in vivo in diabetes (13,14). Similarly, studies in cultured endothelial cells have demonstrated increased superoxide and eNOS expression in response to high glucose (15) and have implicated increased superoxide from mitochondria (2) and uncoupled eNOS (16) in the activation of signaling pathways linked to cell injury.…”

mentioning

confidence: 99%

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Attenuation of Renal Injury in db/db Mice Overexpressing Superoxide Dismutase

et al. 2004

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The effects of overexpression of Cu 2؉ /Zn 2؉ superoxide dismutase-1 (SOD-1) on indexes of renal injury were compared in 5-month-old nontransgenic (NTg) db/db mice and db/db mice hemizygous for the human SOD-1 transgene (SOD-Tg). Both diabetic groups exhibited similar hyperglycemia and weight gain. However, in NTg-db/db mice, albuminuria, glomerular accumulation of immunoreactive transforming growth factor-␤, collagen ␣1(IV) , nitrotyrosine, and mesangial matrix were all significantly increased compared with either nondiabetic mice or SOD-Tg-db/db. SOD-1 activity and reduced glutathione levels were higher, whereas malondialdehyde content was lower, in the renal cortex of SOD-Tg-db/db compared with NTg-db/db mice, consistent with a renal antioxidant effect in the transgenic

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“…Hyperglycemia leads to diabetic nephropathy (DN) via multiple mechanisms, and among them increased aldose reductase (AR) activity [4,5], nonenzymatic glycation and glycooxidation [6,7], activation of protein kinase C (PKC) and hexosamine pathway [8][9][10], arachidonic acid metabolism via 12/15-lipoxygenase pathway [11,12], and triose phosphate accumulation [13] are the best studied. Growing evidence obtained in diabetic animals (primarily, STZ (streptozotocin)-diabetic rats and mice) [14][15][16][17] as well as cell culture models [18][19][20] implicates free radicals and the potent oxidant peroxynitrite (a product of superoxide anion radical reaction with nitric oxide) in both hemodynamic and metabolic abnormalities leading to DN.…”

Section: Introductionmentioning

confidence: 99%

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Drel

Pacher²,

Stevens

et al. 2006

Free Radical Biology and Medicine

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Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADPribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg −1 day −1 ) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetesinduced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM Lglucose or 30 mM D-glucose plus 10 μM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.

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Overexpression of Cu2+/Zn2+ Superoxide Dismutase Protects Against Early Diabetic Glomerular Injury in Transgenic Mice

Cited by 143 publications

References 61 publications

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

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

Attenuation of Renal Injury in db/db Mice Overexpressing Superoxide Dismutase

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

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