The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy

Abstract

IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are rare primary glomerulopathies, though the incidence of IgAN is greater. Endothelin 1 (ET-1) and angiotensin II (Ang II) are implicated in the development and progression of IgAN and FSGS. Both conditions impact health-related quality of life (HRQoL) and may lead to kidney failure. IgAN and FSGS are both evidenced clinically by proteinuria, with a greater degree of such associated with more progressive disease and shorter times to kidney failure. Accordingly, the reduction of proteinuria in patients with these conditions is a key target. Currently, IgAN and FSGS treatments are unsuccessful or only partially successful in a number of patients. Immunosuppressant therapy is first-line for primary FSGS and utilised for patients with IgAN who remain at high risk of progression despite maximal supportive care; however, while effective, there is a significant risk of toxicity and relapse is frequent. A number of clinical trials are ongoing to investigate the use of non-immunosuppressive agents in the management of these conditions. The dual endothelin Type A receptor/Ang II subtype 1 receptor (ETAR/AT1R) antagonist (DEARA) sparsentan is currently being assessed as a means to control kidney disease progression. Interim study results show that sparsentan can lead to greater reductions in proteinuria than AT1R antagonism alone in IgAN and more patients reaching partial remission (PR) in FSGS. Herein, a symposium by leading experts at the European Renal Association (ERA) 59th Congress in Paris, 19th−22nd May 2022, is presented. It highlights IgAN and FSGS and the role of proteinuria in these conditions, and how targeting ET-1 and Ang II can lead to a reduction in proteinuria in IgAN and potential FSGS PR.

Sparsentan: First Approval

“…Endothelin-1 and angiotensin II signalling pathways contribute to the progression of IgA nephropathy [ 16 ]. Sparsentan simultaneously blocks these pathways by binding to endothelin type A and angiotensin II type 1 receptors, with high affinity (Ki 12.8 and 0.36 nM, respectively) and selectivity (> 500-fold over endothelin type B and angiotensin II type 2 receptors) [ 7 ].…”