A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea

Abstract

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg−1·day−1macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO27 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.

Endothelin receptors in renal interstitial cells do not contribute to the development of fibrosis during experimental kidney disease

“…Our findings of an activation of the endothelin system in fibrotic kidney disease is in accordance with previous reports, which demonstrated either an enhanced ET-1 gene expression [1,16,43,44] or an increased ET A gene expression [9,16] in experimentally induced kidney fibrosis. We now extend these findings by showing the localization of increased ET-1 and ET A gene expression.…”

“…ET-1 binds to either ET A -or ET B -R which mainly activate the inositol triphosphate signaling cascade intracellularly [26,50,52]. In damaged kidneys, an increase of ET-1 and ET A -R mRNA expression has been already reported [1,9,33,43,44,65]. An important role of ET-1 in renal fibrosis was elucidated from the finding that transgenic mice overexpressing human ET-1 develop renal abnormalities associated with interstitial fibrosis [25] and that inhibitors of endothelin receptors can attenuate experimentally induced fibrosis [5,45,48].…”

Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta‐analysis of randomized controlled trials

“…On the other hand, as a competitive and specific antagonist for both ET A R and ET B R, bosentan presented an insignificant effect on albuminuria and blood pressure compared with placebo. The insignificant renoprotective effect with bosentan observed in this study is consistent with previous observations that dual ET A / B R blockade has a weaker effect on renal function than selective ET A R blockade 10,27 . As mentioned above, ET A R activation causes vasoconstriction, cell proliferation and extracellular matrix accumulation, whereas ET B R activation promotes antiproliferative and antifibrotic pathways and vasodilation 10,11 .…”

“…The insignificant renoprotective effect with bosentan observed in this study is consistent with previous observations that dual ET A / B R blockade has a weaker effect on renal function than selective ET A R blockade. 10,27 As mentioned above, ET A R activation causes vasoconstriction, cell proliferation and extracellular matrix accumulation, whereas ET B R activation promotes antiproliferative and antifibrotic pathways and vasodilation. 10,11 It is possible that the lack of renoprotective effect was attributable to the blockade of ET B Rs to mask ET A protection by diminishing ET B activation of anti-fibrotic and anti-inflammatory pathways.…”

American Journal of Physiology-Renal Physiology Collections: Hypertension

“…These proteases are capable of causing pathophysiological activation of the epithelial Na + channel, which can result in reduced Na + excretion, fluid retention, and hypertension (7). A study by Morales-Loredo et al (8) found that the next-generation dual endothelin receptor antagonist macitentan was capable of reducing hypertension but not renal dysfunction in a chronic kidney disease-sleep apnea rat model. From a more molecular perspective, F€ ahling et al (3) verified that annexin-A2 nucleic acid binding occurs following angiotensin II stimulation and may be an important transcriptional regulator of angiotensin receptor signaling.…”