Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus

Nakhoul, Farid; Miller‐Lotan, Rachel; Awad, Hoda; Asleh, Rabea; Kheir, Jad; Nakhoul, Nakhoul; Asaf, Roy; Abu-Saleh, Niroz; Levy, Andrew P.

doi:10.1152/ajprenal.90655.2008

Cited by 27 publications

(29 citation statements)

References 43 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

117

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

117

122

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“…We published that haptoglobin (Hp) protein, with different genotypes, Hp1-1, Hp2-1, and Hp 2-2, is an important anti-oxidant in DM patients, especially those with Hp1-1. Increased deposition of iron in the PCT of diabetic mice with Hp2-2 was accompanied by increased production of free radicals compared with diabetic mice with Hp1-1 [9,12].…”

Section: Introductionmentioning

confidence: 99%

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in patients with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and continue to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic alterations interact synergistically, and have been reported to activate local RAAS resulting in increased angiotensin-2. In spite the early and chronic treatment with converting enzyme inhibitors and angiotensin receptor blocking drugs, the number of patients reaching end stage renal disease and replacement therapy are increasing.Recently different pathways were proposed to be involved in the pathogenesis of diabetic nephropathy, including the autophagy process, Klotho and the selective agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the protective autophagic process and increase in cellular damage.α-Klotho is a multifunctional protein highly expressed in the kidney. The klotho protein has endogenous anti fibrotic function via antagonism of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho in early stage of diabetic nephropathy may contribute to the progression of DN by accelerated fibrogenesis.The selective vitamin D agonist and his receptor, play a protective pathway in diabetic nephropathy. A key renoprotective function of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This antiproteinuric effect and the deceleration of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the different new mechanisms involved in diabetic nephropathy and future therapeutic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the selective active vitamin D.

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“…We also propose that the role of Hp in T2DM risk might lies in its ability to act as an antioxidant (Mustafa et al, 2004;Quaye et al, 2006). Free Hb-induced oxidation is more effectively inhibited by Hp1-1 compared with Hp2-2, which has been reported to be a less effective antioxidant in vitro and in vivo (Okazaki and Nagai, 1997;Melamed-Frank et al, 2001;Mustafa et al, 2004;Asleh et al, 2005;Levy et al, 2007;Milman et al, 2008;Nakhoul et al, 2009). With the lower anti-oxidative potential, those with Hp2-2 genotype may therefore have the higher risk for T2DM.…”

Section: Discussionmentioning

confidence: 90%

Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese

Shi

Sun²,

Wang³

et al. 2012

Genetic Testing and Molecular Biomarkers

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The aim of this study was to investigate the association between haptoglobin (Hp) gene polymorphism and occurrence of type 2 diabetes mellitus (T2DM) in a northern Chinese population. We studied the association of the Hp gene polymorphism with T2DM in 584 unrelated T2DM patients and 690 control subjects with normal glucose tolerance among northern Chinese. The patients were diagnosed in accordance with the guidelines of the American Diabetes Association. The clinical characteristics of the study population were recorded, and the Hp genotype was determined. The frequencies of the genotypes in the group of T2DM patients and the controls were as follows: Hp2-2, 51.7% and 44.1%; Hp2-1, 39.7% and 45.1%; and Hp1-1, 8.6% and 10.9%, respectively. There was significant difference for the genotypic and allelic distribution between the two groups ( p = 0.021 and p = 0.007, respectively). Even after readjusting for the confounding effects of age, gender, and body mass index, a significant effect of genotypes on T2DM was still found in the recessive model for the Hp2 allele tested ( p = 0.002). Those who had the Hp2-2 genotype had a significantly higher risk for T2DM than those with other genotypes (odds ratio = 1.441, 95% confidence interval = 1.143-1.817). The results showed that the Hp2-2 genotype is associated with increased risk of T2DM in the northern Chinese Han population.

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Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus

Abstract: Nakhoul FM, Miller-Lotan R, Awad H, Asleh R, Jad K, Nakhoul N, Asaf R, Abu-Saleh N, Levy AP. Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus.

Cited by 27 publications

References 43 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

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese

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