RENAL ENDOTHELIN SYSTEM IN POLYCYSTIC KIDNEY-DISEASE

Polycystic kidney disease (PKD) is characterized by interstitial fibro sis 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, there fore, analyzes the tissue distribut ion of ET-1, the tissue concentrations of ET-1, as well as the express ion 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 correspond ing age-matched Sprague Dawley littermates (SD) (+/+) were analyzed. F urthermore, the acute effects of the mixed (A/B) endothelin receptor a ntagonist bosentan on hemodynamic and renal function were investigated in 6-mo-old, conscious, chronically instrumented (cy/+) rats. The kid neys of affected rats showed significantly elevated tissue levels of E T-1 compared with age-matched controls (3.5 +/- 0.3-fold in young cy/c y 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 demonstrat ed a high ET-1 expression within the epithelial cells of the cysts as well. Scatchard analysis revealed a markedly decreased ETA and ETB rec eptor density in all groups of affected rats. The acute blockade of bo th endothelin receptor subtypes using bosentan in 6-mo-old heterozygou s PKD rats led to a significant decrease in mean arterial BP (MAP) (-1 9.7 +/- 2.1 mmHg, P < 0.05) and GFR (-41 +/- 5%, P <0.005). Renal bloo d flow (RBF) was significantly increased (+2.1 +/- 0.5 ml/min, P < 0.0 5) after bosentan, whereas bosentan had no effect on MAP, GFR, and RBF in age-matched controls. These data show that the paracrine renal end othelin system is activated in PKD and participates in the regulation of MAP, GFR, RBF, and possibly contributes to renal cyst formation and fibrosis.