Endothelin signaling in diabetic kidney disease: therapeutic targeting and translational advances

Diabetic kidney disease (DKD) is the most prevalent microvascular complication of type 2 diabetes mellitus (T2DM) and a leading global cause of end-stage kidney disease (ESKD). Current first-line regimens, including renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter 2 inhibitors, only partially slow the decline in renal function, and a substantial proportion of patients retain residual renal risk. Endothelin-1 (ET-1), a vasoactive peptide produced by intrinsic renal cells, drives the progression of DKD through endothelin A receptor (ETAR)-mediated hemodynamic, podocyte, mesangial, and tubulointerstitial injury, whereas protective endothelin B receptor signaling is impaired. Selective ETAR antagonists reduce albuminuria and kidney events in clinical trials, but fluid retention and heart failure signals limit their routine use, and combination strategies are under evaluation in ongoing phase III trials. ET-1 also serves as a candidate non-invasive biomarker for early DKD detection and prognosis. This narrative review integrates the molecular mechanisms of endothelin system activation, the multilayered renal injury mediated by the ET-1/ETAR axis, the clinical evidence for endothelin receptor antagonists, and the biomarker value of ET-1. We further discuss the potential interface between the gut-kidney axis and the endothelin system, and we outline the research priorities that could translate this pathway into precision therapy for DKD.