The angiotensin II receptors are a class of G protein-coupled receptors with angiotensin II as their ligands. Angiotensin II receptors include four subtypes: AT1, AT2, AT3 and AT4. They are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II. Therefore, they play an important role in the renin-angiotensin system. AT1 receptor mediates most of the effects of angiotensin II, such as vasoconstriction, aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells.
Endothelin receptors are the GPCRs of the β-group of rhodopsin receptors that bind to endothelin ligands. There are at least four subtypes of endothelin receptors, ETA, ETB (ETB1, ETB2) and ETC. Meanwhile, the endothelin family comprises three isoforms, ET-1, ET-2, and ET-3, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ETA receptor. Endothelin receptors can result in elevation of intracellular-free calcium, which constricts the smooth muscles of the blood vessels, raising blood pressure, or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.
Sparsentan (RE-021) is a highly potent dual angiotensin II and endothelin receptor antagonist.
Sparsentan can selectively targeting the endothelin A receptor (ETAR) and the angiotensin II subtype 1 receptor (AT1R). Pre-clinical data shows that blockade of both endothelin type A and angiotensin II type 1 pathways in forms of rare chronic kidney disease, reduces proteinuria, protects podocytes and prevents glomerulosclerosis and mesangial cell proliferation. Therefore, Sparsentan has the potential for focal segmental glomerulosclerosis (FSGS) research. What’s more, Sparsentan dose dependently antagonizes the angiotensin II-induced pressor response. Besides, Sparsentan also shows efficacious and long acting in the big ET-1-induced pressor model.
All in all, Sparsentan is a potent dual angiotensin II and endothelin receptor antagonist with the potential for FSGS research.