ETA receptor blockade induces tubular cell proliferation and cyst growth in rats with polycystic kidney disease.
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.
Hocher
Berthold
B
Department of Nephrology, University Hospital Charité, Humboldt University of Berlin, D-10098 Berlin, Germany. berthold.hocher@charite.de
Kalk
Philipp
P
Slowinski
Torsten
T
Godes
Michael
M
Mach
Alexander
A
Herzfeld
Sophia
S
Wiesner
Doreen
D
Arck
Petra Clara
PC
Neumayer
Hans-H
HH
Nafz
Benno
B
D000818:Animals; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology*; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D011422:Propionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012079:Renal Circulation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; C113044:LU 224332; D010666:Phenylpropionates; D011422:Propionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C107831:darusentan