Genetic Effect of Endothelin and Angiotensin Receptor Blockade on Renal Injury in Salt-Sensitive and Salt-Resistant Hypertension

Proteinuria was inhibited by angiotensin receptor antagonists with a variable response. It remained unclear whether failure of some experimental models of hypertension to respond to treatment with the angiotensin antagonists may be due to genetic background. To investigate genetic effects on renal injuries in response to endothelin-A blocker (ABT-627), endothelin-B blocker (A-192621), and angiotensin receptor blocker (valsartan), we compared deoxycorticosterone acetate (DOCA)-salt rats and spontaneously hypertensive rats (SHR) with the genetic control Wistar-Kyoto rats. Drugs were initiated after hypertension was established. Compared with controls, arterial pressure increased in both strains and was not decreased after 4 weeks’ drug intervention. In both hypertensive strains, renal creatinine clearance decreased, and urinary excretion of protein, interstitial fibrosis, and TGF-β mRNA levels were significantly increased. In vehicle-treated DOCA-salt rats, such damage was overcome by ABT-627 and substantially blunted by valsartan, but not with A-192621. The improvement degree of proteinuria in DOCA-salt rats was significantly greater in rats treated by ABT-627 than those treated by valsartan. In SHR, valsartan, but not ABT-627, can significantly attenuate the renal injury. These results strongly support the important role of genetic predisposition in different renal responses to treatments. In DOCA-salt rats, endothelin-A receptor– and angiotensin receptor-mediated action plays an important role in the pathogenesis of renal damage. On the other hand, only angiotensin receptor antagonist is useful for treatment in SHR.