The Role of Endothelin and Endothelin Antagonists in Chronic Kidney Disease

Abstract

<b><i>Background:</i></b> Endothelins (ET) are a family of peptides that act as potent vasoconstrictors and pro-fibrotic growth factors. ET-1 is integral to renal and cardiovascular pathophysiology and exerts effects via autocrine, paracrine and endocrine signaling pathways tied to regulation of aldosterone, catecholamines, and angiotensin. In the kidney, ET-1 is critical to maintaining renal perfusion and controls glomerular arteriole tone and hemodynamics. It is hypothesized that ET-1 influences the progression of chronic kidney disease (CKD), and the objective of this review is to discuss the pathophysiology, and role of ET and endothelin receptor antagonists (ERAs) in CKD. <b><i>Summary:</i></b> The use of ERAs in hypertensive nephropathy has the potential to decrease proteinuria, and in diabetic nephropathy has the potential to restore glycocalyx thickness, also decreasing proteinuria. Focal segmental glomerular sclerosis has no specific Food and Drug Administration-approved therapy currently, however, ERAs show promise in decreasing proteinuria and slowing tissue damage. ET-1 is a potential biomarker for autosomal dominant polycystic kidney disease progression and so it is thought that ERAs may be of some therapeutic benefit. <b><i>Key Messages:</i></b> Multiple studies have shown the utility of ERAs in CKD. These agents have shown to reduce blood pressure, proteinuria, and arterial stiffness. However, more clinical trials are needed, and the results of active or recently concluded studies are eagerly awaited.

Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review

“…Although most of clinical ER antagonists were highly selective ETA-R blockers, high dosages of such medicine could still block ETB-Rs[ 9 ]. Inhibition of the ETB-R in tubular cells also causes activity of Na + and water transport[ 4 ]. Anemia may ascribe to hemodilution due to fluid retention[ 8 , 24 ].…”

“…In the kidneys, endothelin-1 (ET-1) exerts several physiological effects, including control of water and sodium homeostasis. The ET system is complicated, consisting of a converting enzyme and two active receptors: The ETA (ETA-R) and ETB (ETB-R) receptors[ 4 ]. The activation of ETA-Rs mainly in vascular smooth muscles causes extremely potent vasoconstriction, endothelial dysfunction, insulin resistance, inflammation, and fibrosis.…”

“…The activation of ETA-Rs mainly in vascular smooth muscles causes extremely potent vasoconstriction, endothelial dysfunction, insulin resistance, inflammation, and fibrosis. On the other hand, ETB-Rs, which are mainly expressed in the vascular endothelium, can induce vasodilatation via nitric oxide and prostanoid release[ 4 , 5 ]. Patients with type 2 diabetes have been found to have increased plasma ET-1 Levels, which contribute to endothelial dysfunction[ 6 ].…”

“…Patients with type 2 diabetes have been found to have increased plasma ET-1 Levels, which contribute to endothelial dysfunction[ 6 ]. Several clinical trials have certified that endothelin receptor (ER) antagonists could reduce albuminuria in patients with DN[ 7 , 8 ] and that ETA-R blockers were safe at low dosages and might provide additional benefits to an already existing RAAS blockade[ 4 ]. This suggests that ER antagonists might be a novel and beneficial drug for DN[ 9 ].…”

Therapeutic Insights in Chronic Kidney Disease Progression

“…Several studies in diabetic nephropathy, hypertensive kidney disease, and focal segmental glomerulosclerosis demonstrated that ET-1 inhibition can reduce proteinuria and improve kidney function ( 46 ). In a randomized clinical trial that tested avosentan, an ET-1A inhibitor, against placebo was ended prematurely after 4 months due to an increase in cardiovascular events in the avosentan arm, mainly due to fluid overload and congestive heart failure ( 30 ).…”