The Endothelin System in Polycystic Kidneys of Han:SPRD Rats

Hocher, Berthold; Zart, Rüdiger; Braun, Norbert; Schwarz, Anja; Woude, Fokko van der; Rohmeiss, Peter; Koppenhagen, K

doi:10.1097/00005344-199800001-00095

Cited by 22 publications

(26 citation statements)

References 8 publications

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“…There is also evidence of increased renal endothelin 1 (ET-1) in patients with ADPKD using immunohistochemical staining with an ET-1 antibody. 23 This observation is of interest because angiotensin II is known to stimulate endothelin. 24 Endothelial function also is impaired in patients with ADPKD as compared with patients with essential hypertension and normal control subjects.…”

Section: Sympathetic Activity In Adpkdmentioning

confidence: 99%

Renal Volume, Renin-Angiotensin-Aldosterone System, Hypertension, and Left Ventricular Hypertrophy in Patients with Autosomal Dominant Polycystic Kidney Disease

Schrier¹

2009

Journal of the American Society of Nephrology

124

106

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In the past, autosomal dominant polycystic kidney disease (ADPKD) had been termed adult polycystic disease. Now, however, it is clear that many of the features of ADPKD occur during childhood. In fact, ADPKD has been diagnosed in utero. 1 Very-early-onset ADPKD has been the designation for infants whose diagnosis is made within the first 18 mo of life. 2 As compared with children who receive a diagnosis of ADPKD later, the children with very-early-onset ADPKD have larger kidneys and more renal cysts when adjusted for age. 3 CHILDREN WITH ADPKDThe most consistent characteristic of children with ADPKD is the relationship between renal volume and BP. Children with ADPKD and hypertension, defined as Ͼ95th percentile, have significantly larger kidneys than children who have ADPKD and have BP Ͻ95th percentile. 4 Children with BP between the 75th and 95th percentiles have been designated as having borderline hypertension, whereas BP Ͻ75th percentile is designated as normotension. 4 Children who have ADPKD and either hypertension or borderline hypertension exhibit a left ventricular mass index (LVMI) that is significantly greater than in children with normotension. Children who have ADPKD with hypertension have the largest kidneys by ultrasonography, and there is a highly significant correlation in renal volume with systolic as well as diastolic BP. 4 In a prospective 5-yr follow-up study, children with ADPKD and hypertension demonstrated a progressive increase in renal volume and LVMI. 5 During this 5-yr follow-up, 52% of the children with borderline hypertension developed frank hypertension. Of interest, in contrast to children who have ADPKD with hypertension, who needed more than one antihypertensive agent, the BP in children with borderline hypertension could be well controlled to Ͻ50th percentile by monotherapy with an angiotensin-converting enzyme inhibitor ABSTRACTThe relationship between renal volume and hypertension in autosomal dominant polycystic kidney disease (ADPKD) occurs in childhood. Hypertension is associated not only with increased kidney volume but also with significantly increased left ventricular mass index. Moreover, this increase in left ventricular mass index occurs in children who have ADPKD with borderline hypertension (75th to 95th percentile) and is prevented with angiotensin-converting enzyme inhibitor (ACEI) monotherapy. Progression from borderline to overt hypertension (Ն95th percentile) occurs during a 5-yr follow-up in approximately 50% of children with ADPKD and borderline hypertension. Renal cyst enlargement in ADPKD in adults is associated with stimulation of both the circulating and intrarenal renin-angiotensin-aldosterone system. In addition to hypertension, the resultant angiotensin in ADPKD is a pivotal factor in cyst proliferation and expansion, increased sympathetic and endothelin activity, oxidant injury, and fibrosis. There is a close correlation between the level of hypertension, left ventricular hypertrophy, deterioration of GFR, and the progressive enlargement of the cys...

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Section: Sympathetic Activity In Adpkdmentioning

confidence: 99%

Renal Volume, Renin-Angiotensin-Aldosterone System, Hypertension, and Left Ventricular Hypertrophy in Patients with Autosomal Dominant Polycystic Kidney Disease

Schrier¹

2009

Journal of the American Society of Nephrology

124

106

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“…Homologous recombination at exon-1 of the Pkd2 locus resulted in two pkd2 alleles, ws183 (Ϫ) and ws25 (19 …”

Section: Experimental Animalsmentioning

confidence: 99%

“…Elevated concentrations of immunoreactive ET-1 have been found in ADPKD cyst fluid (16) and immunoreactive ET-1 detected in ADPKD cyst epithelium (17). An increase in renal ET-1 gene expression has been documented in two rodent cystic models (18,19).The availability of new highly selective orally active nonpeptide ET receptor antagonists provided us with useful tools to study ET receptor function in ADPKD (20). Our initial hypothesis was that selective ETB blockade might be beneficial in slowing cystic disease progression because tubular ETB receptors had been shown to mediate mitogenesis (21).…”

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confidence: 99%

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Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Chang¹,

Parker²,

Nahas³

et al. 2007

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2 WS25/؊ ). Four experimental groups (n ‫؍‬ 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD. A utosomal dominant polycystic kidney disease (AD-PKD) causes kidney failure in 10% of all patients who are on renal replacement therapy and is caused by mutations in PKD1 or PKD2 (1). The ADPKD proteins polycystin-1 and polycystin-2 function as a complex and regulate multiple signaling pathways to maintain normal tubular structure and function (2). Although a weak phenotype-genotype correlation for renal survival has been reported for PKD1, it is apparent that nonallelic factors such as genetic modifying loci and/or environmental factors have a greater influence on the cystic phenotype (3,4). These factors probably account for the marked intrafamilial phenotypic variability that sometimes is seen in PKD1 or PKD2 pedigrees (5,6).The endothelins (ET-1, ET-2, and ET-3) are a family of multifunctional peptides with potent effects on BP, renal function, and cellular behavior. Although ET-1 originally was purified as a highly potent endothelial-derived vasoconstrictor (7), many other cell types, especially in the kidney, can synthesize and bind ET-1, suggesting a range of other functions (8,9). Two ET receptor subtypes, ETA and ETB, have been shown to mediate ET-1 action but often with opposing effects (10,11). During development, ET-1 (acting via ETA receptors) and ET-3 (acting via ETB receptors) are essential for the development of neural crest-derived tissues (12,13).Several lines of evidence had suggested that ET-1 might pa...

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“…The assay buffer for binding studies contained 1 mg/mL bacitracin, 100 mmol/L TrisHCl, 5 mmol/L MgCl 2 , and 1 g/L BSA, pH 7.4, in a total volume of 150 L. The 125 I-ET-1 tracer concentration was kept constant at 40 000 counts per minute per tube while the concentration of unlabeled ET-1 was increased from 0 to 25 nmol/L (competition studies with "cold saturation"). Samples from crude plasma membranes were used at a concentration of 0.53 mg protein ⅐ mL Ϫ1 according to Hocher et al 15 Binding studies were performed at room temperature for 120 minutes. Nonspecific binding was assessed in the presence of excess ET-1 (5 mol/L).…”

Section: Binding Assays For Eta and Etb Receptorsmentioning

confidence: 99%

Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension

et al. 1999

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Abstract-The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure-independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (PϽ0.01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (PϽ0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats. (Hypertension. 1999;33:816-822.)

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The Endothelin System in Polycystic Kidneys of Han:SPRD Rats

Cited by 22 publications

References 8 publications

Renal Volume, Renin-Angiotensin-Aldosterone System, Hypertension, and Left Ventricular Hypertrophy in Patients with Autosomal Dominant Polycystic Kidney Disease

Renal Volume, Renin-Angiotensin-Aldosterone System, Hypertension, and Left Ventricular Hypertrophy in Patients with Autosomal Dominant Polycystic Kidney Disease

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension

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