Angiotensin II receptor type 1 (AT1R) + Endothelin receptor type A (ETA)

Class

Dual angiotensin receptor / endothelin receptor A antagonist (same class as sparsentan)

Pathway

Renin-angiotensin system + endothelin system — glomerular proteinuric kidney disease (IgA nephropathy, FSGS, CKD)

This mechanism targets two receptors involved in kidney blood-vessel and filtration biology: the angiotensin II type 1 receptor (AT1R) and the endothelin A receptor (ETA). AT1R is the principal receptor through which angiotensin II raises blood pressure and promotes fibrosis (scarring) within the kidney's filtering units, the glomeruli. ETA responds to endothelin-1, a peptide that constricts blood vessels and independently drives glomerular injury and protein leakage into urine (proteinuria). Because the renin-angiotensin system and the endothelin system act through distinct but overlapping pathways to injure the glomerulus, blocking only one often leaves the other free to sustain damage. A single molecule antagonizing both AT1R and ETA aims to reduce glomerular pressure, limit protein leakage, and blunt fibrotic signaling more completely than blocking either pathway alone. This dual-antagonist approach has been explored in proteinuric kidney diseases such as IgA nephropathy and focal segmental glomerulosclerosis (FSGS), forms of chronic kidney disease characterized by progressive glomerular scarring and loss of filtration capacity. The rationale for combining both activities in one agent, rather than relying on separate drugs for each receptor, is to achieve more consistent, simultaneous inhibition of two converging injury pathways within a single dosing regimen.