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Dual Inhibition of Renin-Angiotensin-Aldosterone System and Endothelin-1 in Treatment of Chronic Kidney Disease

Journal article
Published on March 23, 2016

Topics: Nephrology FSGS Sparsentan Lit review

Contributors:
Komers R, Plotkin H.
Name of Journal:
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology


View Publication
DOI:
10.1152/ajpregu.00425.2015
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Home » Publications » Review: Dual Inhibition of RAS and ET-1 in CKD

Summary

Emerging evidence of dual inhibition of the renin-angiotensin system (RAS) and endothelin-1 (ET-1) for treatment of chronic kidney disease (CKD) shows promising additive antiproteinuric effects1


Aim

This review discusses the evidence behind dual inhibition of the renin-angiotensin system (RAS) and the endothelin (ET) pathway in the treatment of chronic kidney disease (CKD).1 The rationale for the combined inhibition and the potential benefits of dual inhibition of RAS and ET are discussed, and preliminary clinical data are presented.1

RAAS and ET-1 in renal physiology and pathophysiology

RAAS

RAS effectors, such as angiotensin II (Ang II) and aldosterone, play crucial roles in renal physiology and pathophysiology.1-3 Ang II, acting mostly via angiotensin II subtype 1 receptors (AT1R), causes vasoconstriction, increases intraglomerular pressure, promotes glomerulosclerosis and tubulointerstitial fibrosis, and contributes to podocyte dysfunction and proteinuria.1-3 Aldosterone also promotes fibrosis and proteinuria while regulating blood pressure.1,4

Endothelin-1 (ET-1)

Similarly, ET-1 affects renal function and hemodynamics, mainly via endothelin type A and B receptors (ETAR and ETBR).5 It acts as a vasoactive peptide that stimulates renal cell growth, extracellular matrix production, and inflammation, thus contributing to kidney disease development.5 ET-1 acts in multiple renal cell types, including the renal vascular tree, glomeruli, and the tubulointerstitial compartment.5

Interactions and cross-talk between RAAS and ET-1

There are both similarities as well as complex cross-talk between actions of ET-1 and RAS effectors in renal pathophysiology.6,7 For example, Ang II stimulates ET-1 release and expression,6 whereas ET-1 mediates various vascular actions of Ang II.7 In general, the evidence for similarities of actions of ET-1 and RAS effectors in processes related to renal injury provides rationale for dual inhibition of RAS and ET-1.1

Dual inhibition of RAS and ET-1

Earlier clinical trials in the field have been add-on studies–where endothelin receptor antagonists (ERAs) were added to baseline treatments with renin-angiotensin system inhibitors (RASi), such as angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).8-10 Beneficial effects on proteinuria from adding ERAs to RASi have been confirmed in people with Type 2 diabetes and nephropathy.8-10 

Single molecules that inhibit both RAS and ET receptors have been developed and are undergoing clinical development.1 A notable example is sparsentan, which has been evaluated for the treatment of primary focal segmental glomerulosclerosis (FSGS).11 The DUET trial was a randomized, double-blind, dose-escalation study evaluating the antiproteinuric efficacy and safety of sparsentan compared with irbesartan in patients with FSGS.11


Key takeaway

Data suggests that dual inhibition of the RAS and ET-1 pathway shows promise for reducing proteinuria and improving outcomes in patients with kidney disease.1



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DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

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Footnotes

As of September 2024, sparsentan is not FDA-approved for the treatment of FSGS.

ACE, angiotensin-converting enzyme; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1R, angiotensin II subtype 1 receptor; CKD, chronic kidney disease; ERA, endothelin receptor antagonist; ET, endothelin; ETaR, endothelin type A receptor; ETBR, endothelin type B receptor; ET-1, endothelin-1; FSGS, focal segmental glomerulosclerosis; RAS, renin-angiotensin system; RASi, renin-angiotensin system inhibitor.

  1. Komers R, Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-884.
  2. Ruster C, Wolf G. J Am Soc Nephrol. 2011;22(7):1189-1199.
  3. Wennmann DO et al. Semin Nephrol. 2012;32(4):377-384.
  4. Sun GP et al. J Am Soc Nephrol. 2006;17(8):2193-2201.
  5. Kohan DE et al. Physiol Rev. 2011;91(1):1-77.
  6. Emori T et al. Hypertension. 1991;18(2):165-170.
  7. Chen L et al. Hypertension. 1995;26(1):83-88.
  8. Kohan DE et al. J Am Soc Nephrol. 2011;22(4):763-772.
  9. Mann JF et al. J Am Soc Nephrol. 2010;21(3):527-535.
  10. Wenzel RR et al. J Am Soc Nephrol. 2009;20(3):655-664.
  11. Trachtman H et al. J Am Soc Nephrol. 2018;29(11):2745-2754.

MA-SP-24-0107 | September 2024