Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation

Jin, Kyubok; Vaziri, Nosratola D.

doi:10.1007/s10157-013-0851-3

Cited by 18 publications

(13 citation statements)

References 31 publications

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“…Unlike the CORAL trial, selection of patients for renal revascularization in our study was based on clinical grounds of progressive refractory hypertension and renal insufficiency. As we and others have shown, revascularization with recent functional loss can recover GFR 4, 5 (albeit occasionally obscured by a loss of hyperfiltration in the contralateral kidney) and reverse the degree of hypoxia 6 . Despite similar mtDNA copy number at baseline and 3 months after therapy, revascularization was associated with a greater fall in urinary COX3 and ND1 compared to medically-treated patients, implying stabilization or decrease of renal mitochondrial injury.…”

Section: Discussionmentioning

confidence: 62%

“…In spontaneously hypertensive rats, impaired mitochondrial respiration and antioxidant defenses coexist with intrarenal inflammation and oxidative stress 4, 5 . Furthermore, proteins involved in mitochondrial metabolism and oxygen utilization are differentially expressed between hypertensive and control rats 6 , implying a link between hypertension and renal mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients

et al. 2016

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Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes COX3 and ND1 by quantitative-PCR in essential (EH, n=25) and renovascular (RVH, n=34) hypertensive patients, and compared them with healthy volunteers (HV, n=22). Urinary kidney injury molecule (KIM)-1 and neutrophil gelatinase-associated lipocalin (NGAL) served as indices of renal injury. Renal blood flow (RBF) and oxygenation were assessed by multidetector-CT and BOLD-MRI. Blood pressure, urinary NGAL and KIM-1 were similarly elevated in EH and RVH, and estimated glomerular filtration rate (eGFR) lower in RVH versus HV and EH. RBF was lower in RVH compared to EH. Urinary mtDNA copy number was higher in hypertension compared to HV, directly correlated with urinary NGAL and KIM-1, and inversely with eGFR. In RVH, urinary mtDNA copy number correlated directly with intra-renal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared to HV subjects (n=10 each). The change in serum creatinine levels and eGFR 3-months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients

et al. 2016

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“…In kidneys from spontaneously hypertensive rats, mitochondrial membrane potential, nitric oxide synthase, COX activity, and mitochondrial uncoupling protein-2-content were reduced, suggesting that hypertension occurs in concurrence with a decline of kidney mitochondrial function (de Cavanagh et al 2006). Furthermore, expression of SOD-2 is blunted in hypertensive rats, and its deficiency is associated with activation of intrarenal inflammatory and ROS-generating pathways (Jin and Vaziri 2014). Finally, a proteomic analysis of mitochondria isolated from medullary thick ascending limb cells identified seven differentially expressed proteins between hypertensive and control rats involved in mitochondrial metabolism and oxygen utilization (Zheleznova et al 2012).…”

Section: Evidence Of Mitochondrial Injury In Renal Diseasementioning

confidence: 99%

The Emerging Role of Mitochondrial Targeting in Kidney Disease

Eirin

Lerman

2016

Handbook of Experimental Pharmacology

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Renal disease affects millions of people worldwide, imposing an enormous financial burden for health-care systems. Recent evidence suggests that mitochondria play an important role in the pathogenesis of different forms of renal disease, including genetic defects, acute kidney injury, chronic kidney disease, aging, renal tumors, and transplant nephropathy. Renal mitochondrial abnormalities and dysfunction affect several cellular pathways, leading to increased oxidative stress, apoptosis, microvascular loss, and fibrosis, all of which compromise renal function. Over recent years, compounds that specifically target mitochondria have emerged as promising therapeutic options for patients with renal disease. Although the most compelling evidence is based on preclinical studies, several compounds are currently being tested in clinical trials. This chapter provides an overview of the involvement of mitochondrial dysfunction in renal disease and summarizes the current knowledge on mitochondria-targeted strategies to attenuate renal disease.

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“…Beyond direct effects of NO renal oxidative stress and inflammation accompany salt-sensitive hypertension in mice deficient in manganese superoxide dismutase [71], and renal levels of ROS hydrogen peroxide are elevated in DSS rats during high salt intake [72]. Elegant in vivo studies have shown null mutation of the p67 phox subunit of NADPH oxidase, a major source of ROS, attenuates hypertension in the DSS rat, and that dietary salt intake evokes a reduction in renal medullary blood flow and glomerular filtration rate that is blunted in p67 phox -null mice [73].…”

Section: Reactive Oxygen Species and Salt Sensitivitymentioning

confidence: 99%

Renal sodium handling and sodium sensitivity

Frame

Wainford

2017

Kidney Res Clin Pract.

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The pathophysiology of hypertension, which affects over 1 billion individuals worldwide, involves the integration of the actions of multiple organ systems, including the kidney. The kidney, which governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters, is central to long term blood pressure regulation and the salt sensitivity of blood pressure. The impact of renal sodium handling and the salt sensitivity of blood pressure in health and hypertension is a critical public health issue owing to the excess of dietary salt consumed globally and the significant percentage of the global population exhibiting salt sensitivity. This review highlights recent advances that have provided new insight into the renal handling of sodium and the salt sensitivity of blood pressure, with a focus on genetic, inflammatory, dietary, sympathetic nervous system and oxidative stress mechanisms that influence renal sodium excretion. Increased understanding of the multiple integrated mechanisms that regulate the renal handling of sodium and the salt sensitivity of blood pressure has the potential to identify novel therapeutic targets and refine dietary guidelines designed to treat and prevent hypertension.

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Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation

Cited by 18 publications

References 31 publications

Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients

Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients

The Emerging Role of Mitochondrial Targeting in Kidney Disease

Renal sodium handling and sodium sensitivity

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