Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jun 5;138(11):645-662.
doi: 10.1042/CS20240249.

Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease

Donald E Kohan  1 , Patricia W Bedard  2 , Celia Jenkinson  2 , Bruce Hendry  2 , Radko Komers  2
Affiliations
Review

Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease

Donald E Kohan et al. Clin Sci (Lond). .

Abstract

Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.

Keywords: Angiotensin II; Endothelin Type A receptor; Endothelin-1; FSGS; IgA nephropathy; Sparsentan.

PubMed Disclaimer

Conflict of interest statement

D.E.K is a consultant for Chinook Therapeutics and Travere Therapeutics, Inc. P.W.B., C.J., B.H., and R.K. are employees and shareholders of Travere Therapeutics, Inc.

Figures

Figure 1
Figure 1. Chemical structure of sparsentan
Chemical structure of the dual endothelin angiotensin receptor antagonist (DEARA), sparsentan, showing the key structural elements of the molecule responsible for antagonism of each receptor, ETAR and AT1R (adapted from [2]). Adapted from Murugesan N, et al. (2005) J. Med. Chem. 48(1):171–179. Copyright © 2005, American Chemical Society.
Figure 2
Figure 2. Mechanisms of action of sparsentan in the kidney
Schematic presentation of main actions of sparsentan in the kidney associated with long-term nephroprotective effects as observed in preclinical studies. These actions include anti-inflammatory and antifibrotic effects both in glomeruli and the tubulointerstitial compartment, podocyte protection, and preservation of the glomerular glycocalyx, in parallel with beneficial effects on glomerular hemodynamics. Created with Biorender.com by Wilmelenne Clapper. ECM, extracellular matrix; mRNA, messenger RNA.
Figure 3
Figure 3. Sparsentan ETAR and ETBR occupancies (right axis) and plasma concentration* (left axis) over 24 h for a single, daily, 400-mg oral dose at steady-state in the PROTECT study (adapted from [165])
Steady-state PK parameters calculated using population PK values for sparsentan 400 mg in the PROTECT study were used to estimate diurnal changes in receptor occupancy. Sparsentan AT1R occupancy (>95%) consistently exceeds ETAR occupancy (>60% and <90%) over a full 24-h period. ETBR occupancy never exceeds 2%. *PK data are based on population PK model prediction for a patient with IgAN. AT1R, angiotensin II receptor type 1; ETAR, endothelin receptor type A; ETBR, endothelin receptor type B; PK, pharmacokinetics.
See this image and copyright information in PMC

References

    1. Kowala M.C., Murugesan N., Tellew J., Carlson K., Monshizadegan H., Ryan C.et al. . (2004) Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension. J. Pharmacol. Exp. Ther. 309, 275–284 10.1124/jpet.103.055855 - DOI - PubMed
    1. Murugesan N., Gu Z., Fadnis L., Tellew J.E., Baska R.A., Yang Y.et al. . (2005) Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J. Med. Chem. 48, 171–179 10.1021/jm049548x - DOI - PubMed
    1. Rheault M.N., Alpers C.E., Barratt J., Bieler S., Canetta P., Chae D.W.et al. . (2023) Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N. Engl. J. Med. 389, 2436–2445 10.1056/NEJMoa2308550 - DOI - PubMed
    1. Rovin B.H., Barratt J., Heerspink H.J.L., Alpers C.E., Bieler S., Chae D.W.et al. . (2023) Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet 402, 2077–2090 10.1016/S0140-6736(23)02302-4 - DOI - PubMed
    1. Siragy H.M. and Carey R.M. (2010) Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am. J. Nephrol. 31, 541–550 10.1159/000313363 - DOI - PMC - PubMed

MeSH terms

Substances

Grants and funding