Sparsentan Ameliorates Glomerular Hypercellularity and Inflammatory-Gene Networks Induced by IgA1-IgG Immune Complexes in a Mouse Model of IgA Nephropathy

Summary

In an IgA nephropathy mouse model, the protective effects of sparsentan were assessed against vehicle on engineered immune complexes (EIC)-induced glomerular proliferation and gene dysregulation in the kidney¹

Background

IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of kidney failure.² Up to 40% of patients develop kidney failure within 20 years of diagnosis resulting in a reduced life expectancy.¹ There is a need for new therapies to treat IgA nephropathy.¹

Sparsentan is a non-immunosuppressive, single-molecule, Dual Endothelin Angiotensin Receptor Antagonist (DEARA).³

While the nephroprotection potential of sparsentan has been demonstrated in the PROTECT study, research on the mechanism of nephroprotection in IgA nephropathy is still needed.¹

IgA nephropathy is thought to occur in a few steps⁴:

Aim

The objective of this animal study was to assess how sparsentan affects gene expression in glomerular pathways in IgA nephropathy.¹

Approach

Engineered immune complexes (EIC) were formed in vitro and confirmed by an immune-complex assay.¹ The formed EIC were intravenously injected into the mice.¹ The mice were divided into four groups¹:

On Day 12, half of a kidney was excised from the mice.¹ RNA was extracted from the kidneys and analyzed with RNA-Seq.¹ 

Gene expression changes in the EIC mouse models and the effect of sparsentan in preventing or ameliorating EIC-induced profiles were evaluated at the single-gene level and at the network level.¹

Findings

In an IgA nephropathy mouse model, sparsentan protected against EIC-induced glomerular proliferation.¹

Compared to mice who only received PBS, EIC injections increased glomerular cellularity.¹ Sparsentan prevented EIC-induced pathological changes as well as EIC-induced increase in actively proliferating mesangial cells.¹

Sparsentan also improved EIC-activated proinflammatory genes and pathways.¹

The most significant pathways identified were¹:

Expression of genes in these pathways increased with EIC injections, while sparsentan decreased gene expression.¹

Mice injected with EIC exhibited changes in protein kinases and transcription factors compared to mice that received EIC and sparsentan.¹

Sparsentan-treated mice resulted in regulation of downstream hub genes that control mesangial proliferation.¹ Some of these genes were mitogen-activated protein (MAP) kinases, known to control cellular proliferation.¹

There is overlap between EIC-dysregulated and sparsentan-responsive genes in mice, and dysregulated genes often found in patients with IgA nephropathy.¹

Most of the overlapping genes play a role in immune function and inflammation including components of the complement pathway.¹

Key takeaway

This IgA nephropathy mouse model demonstrated that sparsentan targets immune and inflammatory processes, which ultimately protects from mesangial hypercellularity.¹ This multi-target approach may underlie the beneficial effects of sparsentan observed in patients with IgA nephropathy.¹

Footnotes

DEARA, dual endothelin angiotensin receptor antagonist; EIC, engineered immune complex; Gd-IgA1, galactose-deficient IgA1; IgA, immunoglobulin A; IgG, immunoglobulin G; IV, intravenous; MAP, mitogen-activated protein; PBS, phosphate-buffered saline.

MA-SP-24-0085 | September 2024