Targeting endothelin signaling in podocyte injury and diabetic nephropathy-diabetic kidney disease

Despite advances in diabetes management, there is an urgent need for novel therapeutic strategies since the current treatments remain insufficient in halting the progression of diabetic nephropathy-diabetic kidney disease (DN-DKD). This review is mainly addressed on the pivotal role of endothelin-1 in the pathophysiology of DN, with a specific focus on its effects on podocytes and the glomerular filtration barrier. Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury via the activation of endothelin type A and B receptors, that drive the progression of glomerulosclerosis in DN-DKD. Endothelin receptor antagonists, including drugs like atrasentan and sparsentan, have demonstrated nephroprotective effects in experimental models by reducing proteinuria and podocyte injury. The therapeutic potential to slow the progression of DN to end-stage kidney disease (ESKD) of these endothelin receptor antagonists in clinical practice is currently under evaluation. However, fluid retention and increased risk of heart failure associated with endothelin receptor antagonists need careful consideration. This review aims to provide an in-depth analysis of the pathophysiological role of endothelin and the emerging therapeutic implications of targeting this pathway in DN-DKD and discusses efficacy, safety, and the possibility of combining the new generation of endothelin receptor antagonists with the standard treatment of CKD and DN-DKD. © The Author(s) under exclusive licence to Italian Society of Nephrology 2024.