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 (ET_AR) 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 ET_AR 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

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

ET-1 and ET_AR 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; ET_AR, endothelin type A receptor; RAS, renin-angiotensin system; WT, Wilms tumor.

MA-DS-24-0025 | September 2024