Paracrine renal endothelin system in rats with liver cirrhosis

Abstract

1 Liver cirrhosis was induced in rats by CCL1 administration. We analysed the expression of endothelin receptor subtypes in the renal cortex and medulla using Scatchard analysis and receptor autoradiography, and measured plasma as well as renal-tissue endothelin-1 concentrations using a specific radioimmunoassay. Furthermore, we analysed the effects of the non-selective (A/B) endothelin receptor antagonist, bosentan (6 and 100 mg kg-' day-') on mean arterial blood pressure, water and sodium excretion and glomerular filtration rate. 2 Our study revealed an overexpression of the endothelin B receptor (ETB) in the renal medulla of rats with liver cirrhosis (Cir: 2775+299 fmol mg'-; Con:1695+255 fmol mg'-; n= 8; means+s.d., P<0.01), whereas the density of ETB in the cortex and the endothelin A receptor (ETA) in the cortex and medulla were similar in both cirrhotic and control rats. Receptor autoradiography showed that the upregulation of medullary ETB in cirrhotic rats was due to an upregulation of ETB in the inner medullary collecting duct cells. 3 The tissue endothelin-1 concentrations were increased in the renal medulla of cirrhotic rats (Cir:271+68 pg g-'wet wt.; Con: 153+36 pg g-' wet wt., n=8; means+s.d., P<0.01). 4 The glomerular filtration rate was slightly decreased in cirrhotic rats but not altered after bosentan treatment in either cirrhotic or control rats. Bosentan decreased sodium excretion to a similar extent in both cirrhotic and control rats, whereas water excretion was significantly reduced by both dosages of bosentan in cirrhotic rats only (Cir + vehicle: 12.5 + 0.62 ml day-', Cir + 6 mg kg-day'-bosentan: 8.6+1.0 ml day'-; Cir+ 100 mg kg'-day'-bosentan:7.4+0.6 ml day'-; n= 10; means+s.e.mean). 5 We therefore suggest that the upregulation of the medullary ETB in cirrhotic rats is involved in the regulation of water excretion in rats with CCL-induced liver cirrhosis.

Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension

“…12,13,15,16 These data are in agreement with a recent study analyzing cardiac ET-1 gene expression in rats with renovascular hypertension. 20 They demonstrated by in situ hybridization techniques that myocardial ET-1 gene expression is not enhanced in 2K1C hypertensive rats, whereas the ET-1 gene is upregulated within the coronary arteries in these hypertensive rats.…”

“…Measurement of arterial blood pressure was performed as recently described by Hocher et al 12,13 The rats were placed in a retaining box and warmed for 15 minutes until a pulse was detected in the tail. Systolic pressure was measured using a tail cuff and pressure transducer in conjunction with an automatic pressure delivery system and chart recorder (Harvard indirect rat-tail blood pressure system, Harvard Apparatus Ltd).…”

Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

“…For instance, the paracrine renal endothelin system is involved in the regulation of renal blood flow, glomerular filtration rate, and tubular water and sodium reabsorption (1)(2)(3)(4). Furthermore, endothelin-1 (ET-1) 1 is able to stimulate mesangial cell proliferation (5) and seems to be involved in matrix protein biosynthesis in the kidney (For review see reference 6).…”

Influence of the Renal Endothelin System on the Autoregulation of Renal Blood Flow in Spontaneously Hypertensive Rats

“…whereas the same dose of bosentan did not influence these parameters in WKY. These findings, which are in ac Endothclin and Autoregulation o f Renal Blood Flow in SHR cordance with the overexpression of ET-A and ET-B recep tors in the kidneys of SI IR [18], argue in favor of an impor tant role of the ET system in the renal hemodynamic chang es observed in SHR, whereas this system does not seem to play a vital role in the renal regulation of normotensivc or ganisms. However, as we did not observe a change in autoregulation of CBF, it seems likely that the changes in total RBF autoregulation are due to the effects o f bosentan on juxtamedullary and/or medullary vessels.…”

“…The shift of the breakpoint o f RBF autoreg ulation toward higher threshold pressures could well be a specific effect o f bosentan in SHR. In fact we could show [18] that an intravenous injection of bosentan induced sig nificant changes both in mean arterial blood pressure and in RBF. whereas the same dose of bosentan did not influence these parameters in WKY.…”