Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

Abstract

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium‐glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non‐diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non‐DKDs.

Diabetic nephropathy: Ayur‐nutri‐pharmaco approach

“…Endothelin is involved in the activation of pro‐inflammatory and pro‐fibrotic pathways within the kidneys, contributing to the development of renal damage. By antagonizing endothelin receptors, ERAs interrupt these pathological processes, potentially attenuating renal inflammation and fibrosis and preserving renal function (Chung et al., 2023).…”

“…Endothelin is involved in the activation of pro-inflammatory and pro-fibrotic pathways within the kidneys, contributing to the development of renal damage. By antagonizing endothelin receptors, ERAs interrupt these pathological processes, potentially attenuating renal inflammation and fibrosis and preserving renal function(Chung et al, 2023).5.2.5 | Anti-inflammatory agentsThese agents intervene at multiple levels to alleviate the inflammatory cascade prevalent in DN. Firstly, they inhibit the production or activity of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, which are elevated in DN and contribute to renal inflammation, endothelial dysfunction, and fibrosis.…”

Pathomechanisms of Diabetic Kidney Disease

“…ET, a polypeptide, is known as a potent vasoconstrictor [378,379]. It is produced by epithelial and mesangial cells in the kidney and plays a crucial role in regulating blood flow, and glomerular filtration, as well as water, sodium, and acid-base balances [379][380][381]. ET exerts its effects through ET receptors A (ETA) and B (ETB), expressed on various renal components including glomerular podocytes, mesangial cells, and arterioles [379][380][381].…”

“…It is produced by epithelial and mesangial cells in the kidney and plays a crucial role in regulating blood flow, and glomerular filtration, as well as water, sodium, and acid-base balances [379][380][381]. ET exerts its effects through ET receptors A (ETA) and B (ETB), expressed on various renal components including glomerular podocytes, mesangial cells, and arterioles [379][380][381]. ET's activation of these receptors can have detrimental effects on the kidney, contributing to the progression of DKD [382][383][384].…”

Expanding options of supportive care in IgA nephropathy

“…Kidney endpoint (alteration in eGFR) was reported in clinical trials with the selective ER A antagonists atrasentan and avosentan, which were tested for diabetic kidney disease, darusentan, primarily tested for resistant hypertension, and dual ET A /ET B receptor inhibitor bosentan currently approved for pulmonary hypertension. Dual ER A and AT 1 receptor antagonist sparsentan is currently being tested for IgAN and focal segmental glomerulosclerosis [ 34 ].…”