Endothelin receptor A blockade reduces proteinuria and vascular hypertrophy in spontaneously hypertensive rats on high-salt diet in a blood-pressure-independent manner.
The renal endothelin (ET) system is involved in the pathogenesis of kidney fibrosis as well as blood pressure control by regulating tubular sodium excretion. Long-term effects of ETA receptor blockade on blood pressure and kidney function in spontaneously hypertensive rats (SHRs) on a high-salt diet are unknown. We treated SHRs on a 6% (w/v) NaCl sodium diet (SHR-S) for 48 weeks with the ETA antagonist LU 135252 (whose selectivity for ETA is 150 times greater than for ETB) with 10, 30 and 100 mg x kg(-1) x day(-1) or placebo. The ETA antagonist had at no time-point any effect on blood pressure. Glomerular filtration rate was normal in SHR-S and not altered by LU 135252. However, urinary albumin excretion was markedly reduced by the ETA antagonist (SHR-S, 145+/-50 mg/day; SHR-S+10 mg x kg(-1) x day(-1) LU 135252, 33+/-11 mg/day, P<0.05 versus SHR-S; SHR-S+30 mg x kg(-1) x day(-1) LU 135252, 55+/-16 mg/day and SHR-S+100 mg x kg(-1) x day(-1) LU 135252, 32+/-11 mg/day, P<0.05 versus SHR-S at both concentrations). Total urinary protein excretion was likewise significantly reduced by treatment with 10 mg.kg(-1).day(-1) LU 135252 (SHR-S, 0.25+/-0.06 g/day; SHR-S+10 mg x kg(-1) x day(-1) LU 135252, 0.089+/-0.01 g/day, P<0.05 versus SHR-S). The higher dosages of LU 135252 showed only a trend towards reduction of total urinary protein excretion. Computer-aided image analysis after haematoxylin/eosin and periodic acid-Schiff staining revealed that treatment with 10 mg x kg(-1) x day(-1) LU 135252 significantly reduces the media/lumen ratio of intrarenal arteries. Higher dosages of LU 135252 were less effective. Renal matrix protein synthesis in SHR-S was not altered by LU 135252. In conclusion, the renal ET system contributes in a blood-pressure-independent manner to the regulation of urinary protein excretion and renal vascular hypertrophy in SHR-S. Lower doses of the ETA antagonist were more effective, indicating that a potential additional blockade of the ETB receptor using higher doses of LU 135252 seems to oppose the beneficial effects of a sole ETA blockade. Urinary protein excretion is an independent risk factor of chronic renal failure, thus ETA antagonists might be a therapeutic tool to prevent proteinuria-induced chronic renal failure.
Trenkner
Jörg
J
Department of Nephrology, Charité, Humboldt University of Berlin, Schumannstrasse 20-21, 10098 Berlin, Germany.
Priem
Friedrich
F
Bauer
Christian
C
Neumayer
Hans-Hellmut
HH
Raschak
Manfred
M
Hocher
Berthold
B
D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D006984:Hypertrophy; D007676:Kidney Failure, Chronic / Q000188:drug therapy; D010666:Phenylpropionates / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D012079:Renal Circulation; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017673:Sodium Chloride, Dietary; C107831:darusentan