Renal endothelin system in polycystic kidney disease.
Polycystic kidney disease (PKD) is characterized by interstitial fibrosis and formation of renal cysts. Interestingly, interstitial fibrosis and renal cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. This study, therefore, analyzes the tissue distribution of ET-1, the tissue concentrations of ET-1, as well as the expression of ET receptor subtypes in the kidneys of a rat model of PKD: Han:SPRD rats. Six-week-old heterozygous (cy/+) and homozygous (cy/cy), as well as 6-mo-old heterozygous (cy/+) Han:SPRD rats and the corresponding age-matched Sprague Dawley littermates (SD) (+/+) were analyzed. Furthermore, the acute effects of the mixed (A/B) endothelin receptor antagonist bosentan on hemodynamic and renal function were investigated in 6-mo-old, conscious, chronically instrumented (cy/+) rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared with age-matched controls (3.5 +/- 0.3-fold in young cy/cy rats, P < 0.01; 1.4 +/- 0.2-fold in young cy/+ rats, P < 0.01; 6.2 +/- 0.4-fold in old cy/+ rats, P < 0.001) due to a highly increased ET-1 synthesis within the epithelial cells of the cysts. Analyzing tissue sections from patients with typical autosomal dominant PKD demonstrated a high ET-1 expression within the epithelial cells of the cysts as well. Scatchard analysis revealed a markedly decreased ETA and ETB receptor density in all groups of affected rats. The acute blockade of both endothelin receptor subtypes using bosentan in 6-mo-old heterozygous PKD rats led to a significant decrease in mean arterial BP (MAP) (-19.7 +/- 2.1 mmHg, P < 0.05) and GFR (-41 +/- 5%, P < 0.005). Renal blood flow (RBF) was significantly increased (+2.1 +/- 0.5 ml/min, P < 0.05) after bosentan, whereas bosentan had no effect on MAP, GFR, and RBF in age-matched controls. These data show that the paracrine renal endothelin system is activated in PKD and participates in the regulation of MAP, GFR, RBF, and possibly contributes to renal cyst formation and fibrosis.
Hocher
B
B
Department of Nephrology, Humboldt University of Berlin, Germany.
Zart
R
R
Schwarz
A
A
Vogt
V
V
Braun
C
C
Thöne-Reineke
C
C
Braun
N
N
Neumayer
H H
HH
Koppenhagen
K
K
Bauer
C
C
Rohmeiss
P
P
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D000077300:Bosentan; D046508:Culture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan