Endothelin ET(A) receptor blockade prevents the progression of renal failure and hypertension in uraemic rats.
BACKGROUND
Elevated plasma and urine endothelin-1 (ET-1) levels have been reported in renal failure and may be involved in renal disease progression. We investigated whether these changes are related to increased vascular and renal ET-1 production in the pole resection remnant kidney model of chronic renal failure in the rat.


METHODS
Uraemic Wistar rats were prepared by surgical renal mass 5/6 ablation and compared with sham-operated controls (protocol 1). Immunoreactive-ET-1 (ir-ET-1) concentration was measured by radioimmunoassay after sample extraction and purification. To investigate the functional role of ET-1 during the progression of chronic renal failure, uraemic rats (protocol 2) were treated with either the vehicle or the ET-1 type A (ET(A)) receptor antagonist LU135252 (LU).


RESULTS
Systolic blood pressure and serum creatinine, as well as urinary volume and proteinuria, were significantly higher, whereas creatinine clearance was reduced in uraemic rats compared with sham-operated controls. As expected, plasma and urine ir-ET-1 concentrations were increased in uraemic rats (P<0.01) and were related to the increased ir-ET-1 levels in blood vessels and glomeruli (P<0.001). Positive correlation was found between plasma, thoracic aorta and mesenteric arterial bed ir-ET-1 levels and systolic blood pressure, as well as blood vessel hypertrophy. In addition, increased urinary ir-ET-1 excretion correlated with the rise in serum creatinine and proteinuria. In protocol 2, a 3-week treatment period with LU was initiated once uraemia and hypertension were established. In untreated uraemic rats, systolic blood pressure increased further (P<0.05), but this was not the case in LU-treated uraemic rats. At the end of treatment, serum creatinine and proteinuria were significantly lower (P<0.05) and creatinine clearance was higher (P<0.01) in LU-treated rats compared with uraemic-untreated animals. While plasma ir-ET-1 concentration was similar in the two groups, ir-ET-1 concentration in thoracic aorta, mesenteric arterial bed, renal cortex and urine was significantly lower in LU-treated animals (P<0.01). In addition, heart, thoracic aorta and mesenteric arterial wet weight to body weight ratios were also significantly reduced in LU-treated uraemic rats (P<0.05).


CONCLUSIONS
Elevated plasma ET-1 concentration and urinary ET-1 excretion in rats with renal mass ablation are related to enhanced ET-1 production in vascular and renal tissues, thus suggesting an important role for ET-1 in the aggravation of hypertension and vascular hypertrophy as well as in the progression of renal insufficiency. These pathophysiological effects are prevented by treatment with selective ET(A) receptor blockade.
Brochu
E
E
CHUQ, L'Hôtel-Dieu de Québec Hospital and Department of Medicine, Laval University, Quebec, Canada.
Lacasse
S
S
Moreau
C
C
Lebel
M
M
Kingma
I
I
Grose
J H
JH
Larivière
R
R
D000818:Animals; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008297:Male; D009994:Osmolar Concentration; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D014511:Uremia / Q000503:physiopathology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C107831:darusentan