ETA receptor blockade induces tubular cell proliferation and cyst growth in rats with polycystic kidney disease

Abstract

Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 ± 119 [cysts/kidney section ± SD]; LU 135252-treated APKD rats, 1084 ± 314; P < 0.001), cyst surface area (ADPKD rats, 7.97 ± 2.04 [% of total section surface ± SD]; LU 135252-treated ADPKD rats, 33.83 ± 10.03; P < 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 ± 17.3 [BrdU-positive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 ± 286.9; P < 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs.