Spasentan/sparsentan mechanism of action

Endothelin (ET) and angiotensinII (AT) are important mediators of kidney disease. These two systems interact closely, exerting additive pathophysiological effects through the interplay of multiple signaling pathways affecting the renal vasculature, glomeruli, and tubulointerstitium. Dual blockade of AT1 receptors and ETAR exerts anti-inflammatory, anti-proliferative, anti-fibrotic and cytoprotective effects in many forms of kidney disease. Sparsentan/Sparsentan is a dual ET and angiotensin receptor antagonist that has been shown to reduce pathophysiological processes and improve renal injury in cells, animal models, and clinically.

The protective effects of sparsentane in models of renal disease corroborate the large body of evidence gathered over the past few decades regarding the renal pathophysiology of the renin-angiotensin and endothelin systems. In mesangial cells, sparsentanehas anti-proliferative effects and inhibits the production of pro-inflammatory and pro-fibrotic cytokines and extracellular matrix (ECM) proteins, thereby ameliorating corresponding glomerular pathologies such as mesangial proliferative glomerulonephritis or glomerulosclerosis.

In glomerular endothelial cells, sparsantane preserves glycocalyx integrity in several models, a mechanism that may contribute to its antiproteinuric effects. In podocytes, sparsentin inhibits Ca2+ flux, an established marker of podocyte injury, resulting in preservation of nephrin and podocin expression, reduction in oxidative stress, attenuation of foot process effacement, and maintenance of the glomerular basement membrane. Given that sparsentine inhibits IFN-γ, which has been shown to be a key regulator of APOL1 synthesis, the drug may be particularly useful for individuals with FSGS and APOL1 risk alleles.

In the tubulointerstitial compartment, sparsentine improved tubulointerstitial fibrosis, associated with normalization of proinflammatory cytokinemRNA and protein levels, profibrotic mediators, ECM proteins, and complement components. In the renal vasculature, sparsentane may exert a protective glomerular hemodynamic effect by attenuating Ang II and ET-1-mediated constriction of efferent arterioles.