Sparsentan Protects Against Development of Albuminuria and Glomerulosclerosis in the gddY Mouse Model of IgA Nephropathy

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Background: gddY mice are an IgA nephropathy (IgAN) model that develops albuminuria by 8 weeks (W) of age with glomerular IgA, IgG, and C3 deposits and progressive mesangioproliferative glomerulonephritis. A previous study in the ddY mouse model (the predecessor to gddY mice) using the endothelin type A receptor (ETAR) antagonist FR139317 resulted in amelioration of proteinuria and preservation of kidney function. Treatment of ddY mice with the angiotensin II type 1 receptor (AT1R) blocker valsartan resulted in significant protection from glomerulosclerosis (GS) without a significant prevention in proteinuria. We examined the effect of sparsentan (SP), a dual ETAR and AT1R blocker, on development of albuminuria and GS in gddY mice. Methods: 4 W old gddY mice were fed with control (C) chow (n=5) or chow containing 900 ppm (n=10) or 1800 ppm (n=10) SP (180 and 360 mg/kg/day) for 8 W. Albuminuria (U-Alb) was assessed at 4, 6, 8, and 12 W of age and plasma levels of SP were determined at 8 am and 4 pm at 6, 8, and 12 W. Kidney biopsies were taken at the end of the study at 12 W of age and 30 glomeruli/animal were scored for the percentage of GS. Serum IgA and glycosylation of IgA was measured using ELISAs. Results: gddY mice fed SP for 8 W from 4 W of age demonstrated significantly (P<0.05) decreased U-Alb vs mice fed C diet (Fig 1). Development of GS in SP-fed mice was significantly (P<0.05) attenuated vs C diet (Fig 2). Plasma levels of SP taken at 8 am and 4 pm after 8 W of treatment were (mean±SD) 281±107 and 105±62 ng/ml respectively for 900 ppm SP and 774±674 and 304±176 ng/ml respectively for 1800 ppm SP. Weight gain in mice fed SP was not different from mice receiving C diet. There was no difference in serum levels of IgA or aberrantly glycosylated IgA. Conclusions: 8 weeks of treatment with SP significantly attenuated increases in albuminuria and GS associated with the development of IgAN in gddY mice. If translated to the clinic, these data support SP as a new approach to the treatment of IgAN.

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