The Endothelin System and Its Antagonism in Chronic Kidney Disease

Abstract

The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease (CVD) is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Treatments that slow the progression of CKD and improve the cardiovascular risk profile of patients with CKD are needed. The endothelins (ET) are a family of related peptides, of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both CVD and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness and more novel cardiovascular risk factors such as oxidative stress and inflammation. Through these, ET also contributes to endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In particular relation to the kidney, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET likely also is involved in progression of renal disease, and data are emerging to suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.

Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

“…It is implicated in both the development and progression of CKD. 20 Its effects are mediated via two receptors, the ET A and ET B receptors; the major pathologic effects are ET A receptor mediated. 20 We have recently shown that long-term selective ET A receptor antagonist therapy using the orally active drug sitaxentan reduces proteinuria, BP, and arterial stiffness in patients with proteinuric CKD, 21 effects that are potentially renoprotective.…”

“…20 Its effects are mediated via two receptors, the ET A and ET B receptors; the major pathologic effects are ET A receptor mediated. 20 We have recently shown that long-term selective ET A receptor antagonist therapy using the orally active drug sitaxentan reduces proteinuria, BP, and arterial stiffness in patients with proteinuric CKD, 21 effects that are potentially renoprotective. We hypothesized that in this same cohort of patients with CKD, sitaxentan would also reduce levels of serum uric acid, ADMA, and urine ET-1 (as a measure of renal ET-1 production) and so provide broader cardiovascular and renal protection.…”

“…The ET system is upregulated in CKD. 20 There is often reciprocal upregulation of the ET system 20 in circumstances with downregulation of NO system activity. 20 In the current study, baseline plasma ADMA and ET-1 did indeed correlate highly with each other (r 2 =0.56; P,0.01), confirming the reciprocal relationship between the NO and ET systems.…”

“…Additionally, it is not possible to separate independent effects of the ET A antagonist on arterial stiffness and ADMA in this limited number of patients. Because both increased ADMA and arterial stiffness independently contribute to CKD progression and its associated morbidity and mortality, 14,20 ET receptor antagonism offers a potentially attractive novel therapy in CKD with benefits beyond those of lowering BP and proteinuria.…”

Pulmonary Hypertension Complicating Multiple Myeloma

“…[17][18][19][20] The uremic milieu of CKD may also promote pulmonary vasculopathy via endothelial dysfunction with increased levels of endothelin-1 and reduced bioavailability of nitric oxide. 21 Additionally, increased pulmonary vascular calcification as a result of CKD or hypercalcemia in the setting of myeloma has been postulated as a mechanism of PH but has not been confirmed in research studies. 22 …”