Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease

Wang, Dan; Iversen, Johan; Wilcox, Christopher S.; Strandgaard, Svend

doi:10.1046/j.1523-1755.2003.00236.x

Cited by 132 publications

(137 citation statements)

References 30 publications

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“…It is possible that these are secondary to the development of renal cysts (4). The expression of polycystin 1 and polycystin 2 in vascular smooth muscle (5-7) and endothelial cells (8) and the functional alterations of vascular smooth muscle (9,10) and endothelial cells (11,12) with PKD1 or PKD2 mutations raise the possibility of a direct role of these mutations in their pathogenesis. The extent to which changes in renal blood flow (RBF) and vascular remodeling are associated with and possibly contribute to cystic disease progression and functional decline has not been ascertained, in part because of the lack of noninvasive methods.…”

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confidence: 99%

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Torres

King

Chapman

et al. 2007

Clinical Journal of the American Society of Nephrology

151

100

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Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.

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confidence: 99%

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Torres

King

Chapman

et al. 2007

Clinical Journal of the American Society of Nephrology

151

100

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“…Endothelial dysfunction has been shown to predate hypertension and chronic renal insufficiency in ADPKD and therefore appears to be a primary defect (58). However, as hypertension progresses, endothelial dysfunction increases (58).…”

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confidence: 99%

“…Hypertension occurs early and is related to the activation of the renin-angiotensinaldosterone system (RAAS), including its major components angiotensinogen, renin, and angiotensin II, vascular inflammation and chemotaxis, endothelial dysfunction, oxidative stress, and nitric oxide (NO) deficiency (6,8,27,47,(57)(58)(59)(60)(61).…”

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confidence: 99%

Endothelial dysfunction and oxidative stress in polycystic kidney disease

Klawitter

Reed-Gitomer

McFann

et al. 2014

American Journal of Physiology-Renal Physiology

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cular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) Ͼ60 ml·min Ϫ1 ·1.73 m Ϫ2 ] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min Ϫ1 ·1.73 m Ϫ2 ). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR Ͼ60 ml·min Ϫ1 ·1.73 m Ϫ2 showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2␣, PGD2, and PGE2, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD2 and PGF2␣ were associated with reduced eGFR, whereas 8-isoprostane and again PGF 2␣ were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

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“…Hypertension in ADPKD is characterized by relative activation of the reninangiotensin-aldosterone system (RAAS) (20 -22), the sympathetic nervous system (23), endothelin (24), and vasopressin (25,26). Abnormalities in endothelial function, left and right ventricular function, and kidney blood flow are present before loss of kidney function and the development of hypertension, and renal excretion of sodium is reduced early in ADPKD (27)(28)(29)(30)(31)(32)(33)(34)(35). These observations suggest that defects as a result of mutations in the polycystins may result in a vascular phenotype that is specific to ADPKD.…”

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confidence: 99%

Autosomal Dominant Polycystic Kidney Disease

Chapman

2007

Journal of the American Society of Nephrology

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Diagnosis and treatment of autosomal dominant polycystic kidney disease (ADPKD) is rapidly changing. Cellular pathways that involve the polycystins are being mapped and involve the primary cilium, intracellular calcium and cAMP regulation, and the mammalian target of rapamycin (mTOR) pathway. With the use of new imaging approaches, earlier diagnosis of hepatic cystic disease is possible, and measurement of kidney and cystic growth as well as kidney blood flow is possible over relatively short periods. PKD gene type, gender, proteinuria, and the presence of hypertension relate to the rate of kidney growth in ADPKD. On the basis of risk factors for progression to ESRD and the pathogenic roles that intracellular cAMP and mTOR play in cystogenesis, novel therapies are now being tested, including maximal inhibition of the renin-angiotensin system, inhibition of renal intracellular cAMP using vasopressin V2 receptor antagonists, and somatostatin analogues, as well as inhibitors of mTOR. This review addresses the current understanding of the pathogenesis and the natural history of ADPKD; accuracy and reliability of diagnostic approaches in utero, childhood, and adulthood; the value of reliable magnetic resonance imaging to measure disease progression early in the course of ADPKD; and novel therapeutic approaches that are being evaluated in ADPKD.

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Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease

Cited by 132 publications

References 30 publications

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Endothelial dysfunction and oxidative stress in polycystic kidney disease

Autosomal Dominant Polycystic Kidney Disease

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