Dual antagonism of the endothelin A and angiotensin II type 1 receptors protects from glomerular hypercellularity in a model of IgA nephropathy
IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by glomerular deposition of immune complexes (IC) consisting of IgA1 with some O-glycans deficient in galactose (Gd-IgA1) and Gd-IgA1-specific IgG autoantibodies. These IC 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. To address this issue, we developed a model wherein engineered IC (EIC) formed from human Gd-IgA1 and recombinant IgG autoantibody are injected into nude mice to induce glomerular injury mimicking human IgAN. Here, we used this animal model to assess the protective effects of sparsentan, a single-molecule dual antagonist of endothelin A receptor (ETAR) and angiotensin II type 1 receptor (AT1R) (DEARA). Oral administration of sparsentan (60 or 120 mg/kg) to mice intravenously injected with EIC attenuated the EIC-induced glomerular hypercellularity. Overall design: In vitro formed immune complexes were intravenously (i.v.) injected into the lateral tail vein of NCr nude mice, every other day for a total of six injections. Kidneys were harvested the day after last injection for immunohistochemistry and NGS.