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

Abstract

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...

20-HETE Mediates Proliferation of Renal Epithelial Cells in Polycystic Kidney Disease

“…The decreased activity of the EGFR in these studies may be involved in attenuating the proliferative response of the epithelial cells even in the presence of procystic hormonal stimulation by AngII, endothelin, vasopressin, or other growth factors. 8,25,[35][36][37][38] There is recent evidence that the MAPK pathway can activate cytosolic phospholipase A 2 to release AA in vascular smooth muscle cells. 39 It is possible that the increased release of AA leads to higher levels of 20-HETE, resulting in accelerated cell proliferation through the MAPK and/or alternate pathways that have yet to be determined.…”

Endothelium-derived ET-1 and the development of renal injury

“…Furthermore, ET Bselective agonists decreased apoptosis in rat endothelial cells (33) and ET B antagonists lead to increased apoptosis in rat and human endothelial cells (11,32). Cancer studies show that activation of the ET B receptor is considered a survival mechanism (24), whereas the inhibition or loss of the ET B receptor is protective against apoptosis in renal tubular cells of a mouse model of PKD (6) or neurons subjected to hypoxia-ischemia (35). It is clear from all these reports that the ET pathway is involved and that a better understanding of the mechanisms by which ET-1 leads to renal injury, especially renal apoptosis, is needed.…”

Autosomal Dominant Polycystic Kidney Disease

“…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).…”