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Sparsentan Is Superior to Losartan in the gddY Mouse Model 1 of IgA Nephropathy

Journal article
Published on January 25, 2024

Topics: Nephrology IgAN Sparsentan Pharmacological

Contributors:
Nagasawa H, Ueda S, Suzuki H et al.
Name of Journal:
Nephrology Dialysis Transplantation


View Publication
DOI:
10.1093/ndt/gfae021
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Home » Publications » Sparsentan in IgAN Mouse Model

Summary

Sparsentan demonstrated a beneficial nephroprotective effect in an IgA nephropathy mouse model1


Background

Inflammatory signals in IgA nephropathy are thought to play a role in glomerular injury, podocyte loss, and mesangial activation contributing to glomerulosclerosis and interstitial fibrosis.1,2

The renin-angiotensin system (RAS) is thought to play a role in the development of glomerulonephritis,3 providing the rationale for the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) in IgA nephropathy.1 Although considered first-line therapy for patients with IgA nephropathy at risk of progressive kidney injury, chronic kidney disease (CKD) is slowed but not prevented.1 There is an urgent need for novel IgA nephropathy treatments.1

Endothelin type A receptor (ETAR) antagonism is thought to be a novel approach to treating IgA nephropathy, as increased endothelin-1 (ET-1) levels, along with angiotensin II (Ang II), have been observed in IgA nephropathy.1,4,5 Clinical evidence suggests antiproteinuric and nephroprotective effects of ETAR and RAS inhibition.6

Sparsentan, an orally active, single-molecule dual endothelin angiotensin receptor antagonist, has demonstrated superior preservation of kidney function and antiproteinuric effects in clinical studies.7,8 However, more research is needed in the mechanism of nephroprotection of sparsentan.1


Aim

The objective of this study was to assess the mechanisms of nephroprotection of sparsentan versus that of standard of care, losartan, in an experimental IgA nephropathy mouse model.1


Approach

Four-week-old gddY mice, an IgA nephropathy mouse model, were treated with either sparsentan or losartan for 8 or 16 weeks.1

At Week 12 or Week 20, kidney sections was excised from the mice.1 RNA was extracted from the kidneys and analyzed.1


Findings

In the gddY IgA nephropathy mouse model, sparsentan lowered the albumin-creatinine ratio (ACR) more rapidly and to a greater extent than losartan.1

Baseline ACR was significantly different for the sparsentan group compared to the control and losartan group (P<0.01).1 This was likely due to the variability of disease onset in gddY mice.1

ACR across all treated mice decreased compared to the control group, with sparsentan demonstrating a more rapid decrease and to a greater extent.1 Given the differences in baseline ACR, additional statistical analyses were conducted.1 Findings supported the rapid decrease in ACR with sparsentan (P<0.0001).1

Sparsentan protected against development of glomerulosclerosis, podocyte injury, and loss of glomerular glycocalyx.1

Glomerulosclerosis

Sparsentan significantly attenuated the development of glomerulosclerosis compared to losartan (P<0.001).1

Podocyte injury

Both sparsentan and losartan significantly prevented the loss of podocytes (P<0.01 and P<0.05, respectively).1 However, sparsentan demonstrated greater preservation of Wilms tumor (WT)-1-positive cells comparable to the control group.1

Loss of glomerular glycocalyx

Sparsentan also resulted in significant preservation of glycocalyx versus losartan (P<0.001). 1

Sparsentan prevented the upregulation mRNA expression of ET-1, ETAR and angiotensin subtype 1 receptor (AT1R), and proinflammatory genes.1

ET-1 and ETAR were strongly upregulated in gddY control mice (P<0.05), and the increase of AT1R was significant as well (P<0.05).1 Although expression remained high, gene expression was attenuated with sparsentan and losartan (P<0.01).1

Increased mRNA expression of proinflammatory genes was significantly attenuated with sparsentan and losartan (P<0.05).1


Key takeaway

Findings from the gddY mouse model suggest that the dual antagonistic action of sparsentan had a beneficial nephroprotective effect compared with inhibiting AT1R alone.1




Footnotes

ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-creatinine ratio; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1R, angiotensin type 1 receptor; ET-1, endothelin-1; ETAR, endothelin type A receptor; RAS, renin-angiotensin system; WT, Wilms tumor.

  1. Nagasawa H et al. Nephrol Dial Transplant. 2024;gfae021.
  2. Suzuki H and Novak J. Semin Immunopathol. 2021;43:669-678.
  3. Wolf G et al. Nephron Physiol. 2003;93:3-13.
  4. Tycová I et al. Physiol Res. 2018;67:93-105.
  5. Coppo R et al. Am J Kidney Dis. 1993;21:593-602.
  6. Smeijer JD et al. Curr Opin Nephrol Hypertens. 2021;30:456-465.
  7. Heerspink HJL et al. Lancet. 2023;401(10388):1584-1594.
  8. Rovin BH et al. Lancet. 2023;402(10417):2077-2090.

MA-DS-24-0025 | September 2024