Endothelin Blockade in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described.

Long noncoding RNA MALAT1 contributes to pregnancy‐induced hypertension development by enhancing oxidative stress and inflammation through the regulation of the miR‐150‐5p/ET‐1 axis

“…ECs release several factors that modulate angiogenesis and inflammatory responses, and the endothelium is injured in various cardiovascular diseases, including hypertension 32 . ET‐1 is involved in vasoconstriction, fibrosis, and inflammation mainly via the activation of its endothelin A (ET A ) receptors (ETAR) in diabetes 33 . Additionally, ET‐1 increases the expression of vascular endothelial growth factor (VEGF) by SMCs, induces VEGF‐stimulated EC proliferation and invasion via the activation of ETAR, which may open a window for employing endothelin receptor blockers for hypertension treatment 34 .…”

Kidney tubules

“…Thick ascending limbs (TALs) and collecting ducts both express ET B receptors, and stimulation by ET-1 causes inhibition of NaCl transport and stimulation of nitric oxide synthase (NOS). The increased production of nitric oxide inhibits Na + K + -ATPase and epithelial sodium channel (ENaC) within the distal convoluted tubules and the collecting ducts [21]. …”

“…Increased ET-1 levels are believed to be pathogenic in diabetic and nondiabetic CKD, contributing to renal hypoxia, inflammation, and fibrosis [18,21]. These effects are predominantly because ligation of the renal ET A receptor promotes vasoconstriction, cell proliferation, and matrix accumulation [18].…”

Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

“…Endothelin receptor antagonists have been developed for the treatment of multiple cardiovascular diseases, such as hypertension and systemic sclerosis [ 10 , 13 , 14 , 15 ]. Moreover, they also show therapeutic action for glaucoma [ 16 ], preeclampsia [ 17 ], diabetic kidney disease [ 18 ] and ovarian tumors [ 19 ]. Endothelin receptors have been considered to be potential target in the clinical setting [ 20 ].…”