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

• Published in: Journal of the American Society of Nephrology 2003-02, Vol.14 (2), p.367-376
• Main Authors: HOCHER, Berthold, KALK, Philipp, SLOWINSKI, Torsten, GODES, Michael, MACH, Alexander, HERZFELD, Sophia, WIESNER, Doreen, ARCK, Petra Clara, NEUMAYER, Hans-H, NAFZ, Benno
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Disease Progression; Endothelin Receptor Antagonists; Fibrosis; Kidney - drug effects; Kidney - pathology; Kidney Tubules - pathology; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; Organ Size - drug effects; Phenylpropionates - pharmacology; Polycystic Kidney Diseases - metabolism; Polycystic Kidney Diseases - pathology; Polycystic Kidney Diseases - physiopathology; Propionates - pharmacology; Pyrimidines - pharmacology; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Renal Circulation - drug effects; Tumors of the urinary system
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1097/01.ASN.0000042165.63601.65

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.