Endothelins and liver cirrhosis

Abstract

Endothelins are a family of 21‐amino acid oligopeptides, called endothelin‐1 (ET‐1), endothelin‐2 (ET‐2), and endothelin 3 (ET‐3). Endothelins act on hepatocytes, liver endothelial cells, and Kupffer cells in a paracrine or autocrine manner through two G protein‐coated receptors, called endothelin A and B receptors, which are mainly located in interlobular veins, interlobular artery endothelial cells and hepatic stellate cells (HSCs). ET B receptor (ETBR)‐1 is responsible for the induction of endothelial nitric oxide synthase, resulting in nitric oxide release and vasodilatation, whereas ETBR‐2 is located on HSCs and is responsible for vasoconstriction. Endothelins are not stored in the organs. Approximately 20% of endothelins are secreted into the circulation system, and are rapidly cleared by the lungs, liver, heart, and kidneys. As a potent vasoconstrictor, endothelins may have a key role for the treatment of hypertensive vascular diseases, inflammation, fibrosis, and metabolic diseases. By clearing ET‐1 from the circulation, endothelin A receptor (ETAR) antagonists can reduce intraportal vascular resistance by dilatating the portal vein, reducing the contraction of HSCs, increasing the diameter of sinusoids, facilitating the regression of liver fibrosis, and restoring liver parenchyma. ET‐1 induces nitric oxide synthase and upregulates cyclooxygenase 2 mRNA levels, making it a key factor during the onset of fibrosis and in the prognosis of patient outcomes. Endothelins can be used to treat porto‐pulmonary hypertension, portal hypertension, angiogenesis, and liver fibrosis and have been approved for the treatment of porto‐pulmonary hypertension. Endothelins are produced on mesangial cells, podocytes, tubular epithelium, and renal collecting tubes in high amounts. Activation of ETAR supports the progression of kidney diseases, whereas activation of ETBR has protective effects on the kidneys. ET‐1 plays an important role in normal cardiovascular homeostasis. Endothelins are closely associated with severe systemic hypertension, congestive heart failure, atherosclerosis, and pulmonary hypertension. Dual ET receptor antagonists reduce blood pressure, but have several side effects, including liver toxicity, acute liver failure, accumulation of salt and water, testicular toxicity, headache, and teratogenicity. Liver enzymes should be checked in all patients who have received ET receptor antagonists, and women of childbearing years should use contraception.

GPCRs and fibroblast heterogeneity in fibroblast‐associated diseases

“…Also inhibits collagen synthesis, proliferation, and transdifferentiation of HSCs a [108] Endothelin receptor type B (ETBR) G s , G i , G q Upregulated in fibrotic condition and activation increases HSC contraction. The interplay of ETRs in the condition warrants exploration [109] Sphingosine-1-phosphate receptor 1 (S1PR1) G i Leads to differentiation of bone marrow mesenchymal stem cells (BMSCs) to myofibroblasts, mediating liver fibrogenesis [110] Sphingosine-1-phosphate receptor 2 (S1PR2) G i , G q , G 12/13 Promotes neutrophil activation and inflammation. Also, macrophage S1PR2 in the liver upregulates NLRP3 inflammasome inducing fibrogenesis [110,111] Sphingosine-1-phosphate receptor 3 (S1PR3) G i , G q , G 12/13 Mediates bone marrow monocyte (BMM) motility and their activation fostering hepatic fibrosis [110] Sphingosine-1-phosphate receptor 4 (S1PR4) G i Activation of NLRP3 inflammasome in hepatic macrophages stimulates the development of liver fibrosis [110] Cannabinoid receptor 1 (CB1) G i Mediates HSC proliferation and is positively correlated to the expression of fibrosis-mediated genes ACTA2, TIMP-1, and MMP-13 a…”

Kidney disease in patients with chronic liver disease: Does sex matter?

“…As described, females express fewer endothelin-A receptors than males and prolonged ET-1 activity is associated with the release of inflammatory cytokines, including TNF-α and IL-6, in smooth muscle cells in the vasculature and mesangial cells in the kidney[ 73 - 75 ]. This calls to question whether ET-1 promotes local inflammation at the level of the renal vasculature and whether that inflammation contributes to sex differences in HRS incidence and treatment response[ 76 ]. Tissue hypoxia is known to increase local inflammation in the kidney[ 77 ].…”