Antioxidant SOD Mimetic Prevents NADPH Oxidase-Induced Oxidative Stress and Renal Damage in the Early Stage of Experimental Diabetes and Hypertension

Peixoto, Elisa; Pessôa, Bruno Sevá; Biswas, Subrata Kumar; Faria, José B. Lopes de

doi:10.1159/000163767

Cited by 70 publications

(70 citation statements)

References 109 publications

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“…[36][37][38][39] As a major cellular source of ROS, the role of Nox family members in mediating the renal complications of diabetes has become increasingly the focus of investigation. However, it remains unclear which of the Nox isoforms is the primary source of ROS in kidney disease.…”

Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

112

122

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NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5 pod+ ). Nox5 pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5 pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension. Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier. 1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction. Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important. [3][4][5][6] Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the

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Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

112

122

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“…Along with the reversal of the redox balance, tempol treatment improved renal functional and structural alterations, as evidenced by decreased albumin excretion rate and renal cortical expression of collagen IV. 90 In a different study, it was found that longterm green tea consumption ameliorates renal injury in hypertensive diabetic rats by inhibiting oxidative stress through downregulation of Nox4 expression. 91 The presence of hypertension exacerbates retinopathy in diabetic animals.…”

Section: Inflammation and Oxidative Stress As The Underlying Mechanismentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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“…It is evident from the present study that administration of CoQ10 to db/db mice is beneficial for preventing diabetes-induced alterations in both mitochondrial and kidney functions. The intrarenal antioxidant defence system is reduced in several animal models of both types of diabetes, including the db/db mice [45], streptozotocin-induced diabetic rats [46] and C57BL/6-Akita mice [47]. It must be taken into consideration that the level of CoQ10 in db/db mice is approximately 20% higher than in controls (G Dallner, unpublished observation) but the level of oxidative stress in db/db mice clearly exceeds the antioxidant defences, thus making CoQ10 supplementation favourable.…”

Section: Q10mentioning

confidence: 99%

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Persson¹,

Franzén²,

Catrina

et al. 2012

Diabetologia

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Aims/hypothesis Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. −1 ). UCP-2 protein levels were similar in untreated control and db/db mice (67± 9 vs 67± 4 optical density; OD) but were reduced in CoQ10 treated groups (43±2 and 38±7 OD). Conclusions/interpretation db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

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Antioxidant SOD Mimetic Prevents NADPH Oxidase-Induced Oxidative Stress and Renal Damage in the Early Stage of Experimental Diabetes and Hypertension

Cited by 70 publications

References 109 publications

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

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