Endothelin System in Hypertension and Chronic Kidney Disease

Abstract

ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ET_A and ET_B receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.

Keywords: diabetic nephropathies; endothelin receptor antagonists; glomerulosclerosis, focal segmental; vascular remodeling.

Figure 1.

The vascular endothelin system is depicted. Endothelin-1 produced in endothelial cells from proET-1 acts on vasoconstrictor ET_A receptors and on underlying vascular smooth muscle in the wall of blood vessels. ET-1 is also secreted abluminally into the bloodstream and acts on endothelial ET_BR (autocrine effect) to stimulate production of nitric oxide and prostacyclin. Ang II, angiotensin II; AVP, arginine vasopressin; ET_AR, ET_A receptor; ET_BR, ET_B receptor; ET-1, endothelin-1; Hb, hemoglobin; NO, nitric oxide; PGI₂, prostacyclin; TBF𝛽, transforming growth factor beta. Created with BioRender.com.

Figure 2.

Intracellular signaling pathways of endothelin receptors leading to hypertrophic vascular remodeling. Occupancy of the endothelin receptor stimulates via G-protein phospholipase C, producing inositol trisphospate that releases calcium from calcium stores leading to calmodulin activation and contraction of smooth muscle in the vascular wall. As well, diacylglycerol is produced and PKC stimulated. ROS are generated mainly by stimulation of NADPH oxidase but also xanthine oxidase, mitochondria, and uncoupled NO synthase, together with growth factor receptor transactivation, and ras-raf-MAPK cascade and non-receptor tyrosine kinase stimulation. Calcium together with reactive oxygen species and stimulation of the MAPK cascade, PKC and non-receptor tyrosine kinases lead to growth and hypertrophic vascular remodeling. Ca⁺⁺, calcium; DG, diacylglycerol; IP₃, inositol trisphosphate; NADPH oxidase, reduced nicotinamide adenine dinucleotide phosphate oxidase; PKC, protein kinase 3; PLC, phospholipase C. Created with BioRender.com.

Figure 3.

The effects of ET-1 and its receptors in the kidney collecting duct are shown. ET-1 generated in the principal cells of the collecting ducts released into the renal interstitium stimulates ET_BR to activate NO synthase, leading to increased generation of NO, which stimulates soluble guanylate cyclase that produces cGMP. The latter inhibits ENaC, inducing thus nartriuresis. ET_AR may also stimulate NO generation. ENaC, epithelial Na⁺ channel; sGC, soluble guanylate cyclase; cGMP, guanosine 3’,5’-cyclic monophosphate. Created with BioRender.com.

Figure 4.

Major glomerular effects of ET-1 and its receptors in chronic kidney disease are depicted. ET-1 produced in endothelial cells and podocytes acts on ET_AR to stimualte rpduction of reactive oxygen species, which contributes to cytoskeletal rearrangement, podocyte effacement and loss of barrier proteins, as well as increased fibrosis. Created with BioRender.com.