Sparsentan ameliorates glomerular hypercellularity and inflammatory-gene networks induced by IgA1-IgG immune complexes in a mouse model of IgA nephropathy

Abstract

IgA nephropathy (IgAN), is characterized by glomerular deposition of immune complexes (IC) consisting of IgA1 with O-glycans deficient in galactose (Gd-IgA1) and Gd-IgA1-specific IgG autoantibodies. These ICs induce kidney injury, and in the absence of disease-specific therapy, up to 40% of IgAN patients progress to kidney failure. IgA1 with its clustered O-glycans is unique to humans, which hampered development of small-animal models of IgAN. Here, we used a model wherein engineered IC (EIC) formed from human Gd-IgA1 and recombinant human IgG autoantibody are injected into nude mice to induce glomerular injury mimicking human IgAN. In this model, we assessed the protective effects of sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) vs. vehicle on EIC-induced glomerular proliferation and dysregulation of gene expression in kidney. Oral administration of sparsentan (60 or 120 mg/kg daily) to mice intravenously injected with EIC attenuated the EIC-induced glomerular hypercellularity. Furthermore, the analysis of changes in the whole kidney transcriptome revealed that key inflammatory and proliferative biological genes and pathways that are upregulated in this EIC model of IgA nephropathy were markedly reduced by sparsentan, including complement genes, integrin components, members of the MAP kinase family, and Fc receptor elements. Partial overlap between mouse and human differentially expressed genes in IgAN further support the translational aspect of the immune and inflammatory component from our transcriptional findings. In conclusion, our data indicate that in the mouse model of IgAN, sparsentan targets immune and inflammatory processes leading to protection from mesangial hypercellularity.

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

“…RNA sequencing analysis of kidney biopsies taken at the end of the study revealed that up-regulation of key inflammatory and proliferative genes and pathways was markedly attenuated by sparsentan treatment, including complement genes (C1q [complement C1q]), integrin components (Itgb2 [integrin subunit beta 2]), members of the MAP kinase family (MAPK1/3/8/14), and Fc receptor elements (Fcer1g [Fc epsilon receptor Ig]) (date on file; Travere). Moreover, translatability of the transcriptional findings for the immune and inflammatory pathways was supported by partial overlap between differentially expressed murine and human genes in patients with IgAN [124].…”

“…Given the ability of sparsentan to inhibit IFN-γ [146], which has been shown to be a key regulator of APOL1 synthesis, the drug may be particularly useful in individuals with FSGS and APOL1 risk alleles. • In the tubulointerstitial compartment, sparsentan ameliorated tubulointerstitial fibrosis in association with normalization of proinflammatory cytokine mRNA and protein levels, profibrotic mediators, ECM proteins, and complement components [124,125,144]. • In the renal vasculature, sparsentan likely exerts protective glomerular hemodynamic effects through mitigation of Ang II-and ET-1-mediated efferent arteriolar constriction [138,139].…”

Advancements in understanding the role of intestinal dysbacteriosis mediated mucosal immunity in IgA nephropathy

“…In a mouse model of IgAN (gddY), sparsentan slowed the progression of acute kidney injury and glomerulosclerosis, demonstrated a faster anti-proteinuric effect, and significantly protected podocytes and the endothelial glycocalyx, though it had no significant impact on circulating IgA levels [ 208 ]. Additionally, Reily et al [ 209 ] evaluated the protective effects of sparsentan on IgAN by using engineered immune complexes (EIC) to induce glomerular injury in mice, simulating human IgAN. They found that sparsentan significantly reduced EIC-induced glomerular hyperplasia and abnormal expression of inflammatory genes at doses of 60 mg/kg and 120 mg/kg.…”