ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Hocher, Berthold; Kalk, Philipp; Slowinski, Torsten; Godes, Michael; Mach, Alexander MachA.; Herzfeld, Sophia; Wiesner, Doreen; Arck, Petra C.; Neumayer, Hans‐H.; Nafz, B.

doi:10.1097/01.asn.0000042165.63601.65

Cited by 39 publications

(35 citation statements)

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“…Our results are reminiscent of the contrasting effects of sodium bicarbonate administration on cyst formation in the Han:SPRD rat (beneficial) but not in other models, such as CD1-pcy/pcy, Pck rat, or the Pkd2 WS25/Ϫ mouse (26,50,51). ETA blockade in the Han:SPRD PKD rat also resulted in an increase in tubular apoptosis and interstitial fibrosis (48). These features were not observed in Pkd2 WS25/Ϫ mice ( Figures 3 and 4) and further suggest different underlying mechanisms of cyst growth or disease progression between the two models.…”

Section: Discussionmentioning

confidence: 47%

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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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Section: Discussionmentioning

confidence: 47%

“…Male heterozygous (cy/ϩ) Han:SPRD rats that were treated with a different ETA antagonist (LU135252) developed increased tubular cell proliferation and an associated increase in cyst growth (48). Although we observed a similar increase in tubular cell proliferation after ETA blockade, the overall effect on cyst progression was neutral.…”

Section: Discussionmentioning

confidence: 49%

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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“…In 1990, cloned cDNA sequences of two receptors for endothelin were published (7,8). When cells were transfected with the cloned cDNA, 125 I-labelled ET-1 was displaced from one receptor by all three peptides with ET-1 displaying the highest potency (7) whilst all three isopeptides displayed similar potencies in displacing 125 I-labelled ET-1 from the other receptor (8). These two receptors are respectively what are now known as the ET A and ET B receptors and are classified on the basis of their rank order of potencies for the endothelins, being ET-1 = ET-2 ≫ ET-3 for the ET A receptor and ET-1 = ET-2 = ET-3 for the ET B receptor (9).…”

Section: Endothelin Receptorsmentioning

confidence: 99%

“…The renal endothelin system is activated in autosomal-dominant polycystic kidney disease (ADPKD) and is considered to be a disease-modifying factor (124). ET-1 seems to promote cyst-formation, and furthermore, ET A receptor blockade has been shown to increase cyst formation in the Han:SPRD rat, an animal model of ADPKD (125). In most, but not all, models of renal disease, however, selective ET A receptor blockade as well as non-selective blockade have both been shown to be beneficial (see Table 3).…”

Section: Kidney Diseasementioning

confidence: 99%

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

Schneider

Boesen

Pollock

2007

Annu. Rev. Pharmacol. Toxicol.

257

247

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First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET A and ET B , which usually have opposing actions, mediate the actions of endothelin. ET A receptors function to promote vasoconstriction, growth, and inflammation while ET B receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET A selective or non-selective ET A /ET B receptor antagonists would be useful in a range of clinical settings. Keywordsreceptor localization; pulmonary hypertension; heart failure; chronic kidney disease Shortly after it was discovered that the vascular endothelium releases a peptide capable of profound vasoconstriction, a considerable amount of attention was paid to the potential actions of endothelin in the pathogenesis of cardiovascular disease. We have since learned a great deal about how this paracrine factor influences function in an extremely wide range of areas including neurotransmission, cell growth and epithelial transport, just to name a few. This myriad of activities has allowed the endothelin system to garner a tremendous amount of attention from the pharmaceutical industry with the development of numerous receptor specific and non-specific antagonists as well as efforts to identify drugs that inhibit endothelin synthesis. This work has led to new therapeutic approaches to pulmonary arterial hypertension and most likely other diseases in the not too distant future. In addition to this enormous drug discovery effort, it has also become clear that endothelin plays an important physiological role in maintaining blood pressure homeostasis, for example, by facilitating the excretion of a high salt diet. Because of the almost bewildering range of actions of the endothelin peptides, we limit this review to focus on the receptor-specific cardiovascular actions of endothelin. ENDOTHELIN PEPTIDESEndothelin-1, a 21-amino-acid long peptide first isolated from the supernatant of cultured endothelial cells, is perhaps the most potent vasoconstrictor substance known (1). The human Address for Correspondence: David M. Pollock, Ph.D., Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912-2500, +1-706-721-8517 office, +1-706-721-9799 fax, dpollock@mcg.edu. NIH Public Access Author ManuscriptAnnu Rev Pharmacol Toxicol. Author manuscript; available in PMC 2010 February 22. P...

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“…However, animal studies in ADPKD models have not been encouraging. In the Han:SPRD rat model, administration of the moderately selective endothelin Areceptor antagonist darusentan resulted in increased cyst number and size (60). In Pkd2 WS25/2 mice, the highly selective endothelin A blocker atrasentan was effective in blocking the pressor effects of endothelin-1, but no changes were seen in systolic BP and nominal (although not statistically significant) increases were seen in renal weight, cyst area, and renal fibrosis score (61).…”

Section: Questionsmentioning

confidence: 97%

A Young Patient with a Family History of Hypertension

Peixoto¹

2014

Clinical Journal of the American Society of Nephrology

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The evaluation of causes of hypertension in young adults with a family history of hypertension needs to be methodical to identify potentially treatable causes. Renal-and renovascular imaging and measurement of plasma aldosterone and plasma renin activity are at the core of this evaluation in most patients. Pertinent aspects of hypertension in autosomal dominant polycystic kidney disease are discussed with a focus on the role of the endothelium in mediating early hypertension and a review of treatment strategies. Finally, the possibility that autosomal dominant polycystic kidney disease and primary aldosteronism are connected beyond coincidence is explored; evidence to support it is scant, although there is a likely role for aldosterone excess and the resultant hypokalemia in promoting cyst growth.Clin J Am Soc Nephrol 9: 2164-2172, 2014. doi: 10.2215/CJN.02240314 Case PresentationA 36-year-old white man presented for the evaluation of hypertension, hypokalemia, and biochemical evidence of aldosterone excess. His hypertension was first diagnosed at 22 years of age while in the military, and we do not have records of his evaluation at that time. He reported that he had BP levels in the 150/100-mmHg range and that his weight at that time was approximately 180 lb (body mass index [BMI] approximately 24.5 kg/m 2 ). He was treated with lisinopril with prompt and sustained achievement of BP control.He left the military when he was 26 years old, and his new physician performed an evaluation of his hypertension. He was asymptomatic. He reported a family history of hypertension starting in early adulthood in his brother, mother, one maternal uncle, and maternal grandfather. He was not aware of any history of strokes, kidney disease, endocrine tumors, or hypokalemia, although he had been estranged from his parents since early childhood, and therefore, the information about his family was not complete.His BP was 128/84 mmHg. Other than being overweight (218 lb; BMI529.4 kg/m 2

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ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Cited by 39 publications

References 34 publications

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

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

Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease

A Young Patient with a Family History of Hypertension

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ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Cited by 39 publications

References 34 publications

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

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

Contrasting Actions of Endothelin ETAand ETBReceptors in Cardiovascular Disease

A Young Patient with a Family History of Hypertension

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Contrasting Actions of Endothelin ET_Aand ET_BReceptors in Cardiovascular Disease