Drug Discovery for Overcoming Chronic Kidney Disease (CKD): The Endothelin ETB Receptor / Nitric Oxide System Functions as a Protective Factor in CKD

Accelerated cardiovascular disease (CVD) is a frequent complication of renal disease. Chronic kidney disease (CKD) develops hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. There is general agreement that endothelin-1 (ET-1), which acts through the two subtypes of receptor ET(A) and ET(B), plays important physiological roles in the regulation of normal cardiovascular function and that excessive ET-1 production is linked to CVD and CKD. Although selective ET(A) or nonselective ET(A)/ET(B) receptor antagonisms have been recognized as a potential strategy for treatment of several cardiovascular disease, it remains unclear which of the antagonisms is suitable for the individuals with CKD because upregulation of the nitric oxide (NO) system via ET(B) receptor is responsible for renal function such as natriuresis, diuresis, and glomerular hemodynamics. Our findings clearly indicate that the blockade of ET receptors, in particular ET(A)-receptor antagonism, not only produces a potential renoprotective effect in CKD but also reduces the risk of CVD. In contrast, pharmacological blockade or genetic deficiency of ET(B) receptor seems to aggravate CKD and CVD in several experimental models of rats. Moreover, preliminary evidence in patients with CKD also suggests that both selective ET(A)- and nonselective ET(A)/ET(B)-receptor blockade decreases blood pressure but that selective ET(A) blockade has additional desirable effects on renal hemodynamics. Thus, at least in CKD, these findings support the notion that ET(B) receptor-mediated actions produce a renoprotective effect and that nonselective ET(A)/ET(B)-receptors blockade seem to offer no advantage over selective ET(A) antagonism, and if anything may potentially reduce the benefits.