The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses

Abstract

Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists.

Mechanisms Contributing to Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl

“…Notably, these animals experience acute increases in weight and blood pressure coupled with reduced urinary excretion of sodium and water. These effects are associated with acute activation of the epithelial sodium channel, which is expressed in the collecting ducts of the kidney, reabsorbs sodium, and promotes fluid retention [27]. Further, the endothelin pathway has been identified as a target of NF-κB, with ET A expression decreased in renal artery organ cultures treated with direct NF-κB inhibitors [28].…”

Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice

“…Since many fibrotic features appear to be promoted by ETA receptors [33,35,36], we tested the effect of highly selective ETA receptor blockade in BLM-induced murine lung inflammation and fibrosis. Although nonselective ET-1 receptor inhibition improves the BLM lesion in rodents, there is a theoretical advantage to preserving ETB receptor signaling [11][12][13], since endothelial ETB receptor promotes vasodilatory and anti-inflammatory actions and clears ET-1 from the pulmonary circulation [37,38]. Despite encouraging preclinical results, however, several randomized control trials using nonselective or modestly selective ETA receptor antagonists in IPF patients showed no benefit [39][40][41][42].…”

“…ET-1, a 21-amino acid peptide, along with ET-2 and ET-3, consists of the tree isoforms of the endothelin family [11]. ET-1 unfolds its actions through 2 receptors, ETA and ETB, producing opposite effects on the pulmonary circulation [11]. The endothelin system seems to participate in the pathogenesis of IPF [12,13] by enhancing epithelialmesenchymal transition, fibroblast contractility, and collagen production, as documented by human and animal studies [14,15].…”

“…Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogenic agent with profibrotic properties. ET-1, a 21-amino acid peptide, along with ET-2 and ET-3, consists of the tree isoforms of the endothelin family [11]. ET-1 unfolds its actions through 2 receptors, ETA and ETB, producing opposite effects on the pulmonary circulation [11].…”

“…However, the effect of highly selective ETA blockade in fibrosis models is so far unknown. We thus used sitaxentan, a highly selective, almost specific, ETA receptor antagonist (selectivity up to 6,500-fold) [11] in the bleomycin (BLM) mouse model. This animal model is widely used and is often regarded as the standard in modeling pulmonary fibrosis [21], since it reproduces its key features, including restrictive lung mechanics, epithelial cell injury, ECM deposition, and subpleural fibrosis [22].…”