Selective Peroxisome Proliferator-Activated Receptor γ Modulator, GQ-16, Provides Therapeutic Efficacy in a Murine Model of Rapidly Progressive Glomerulonephritis

Background: Rapidly proliferating glomerulonephritis (RPGN) is clinically characterized by rapid decrease in glomerular filtration accompanied with pathologic findings of glomerular epithelial hypercellularity. It often leads to irreversible kidney failure and is a significant health problem globally. Current treatments for RPGN focus on suppressing the immune system, but they are not curative and have serious side effects. Therefore, safer and more effective therapies are needed. We have previously demonstrated therapeutic potential of GQ-16, a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), in minimal change disease model. We hypothesized that GQ-16 can also provide therapeutic efficacy in a more severe and immunological model of RPGN. Methods: RPGN was induced by two doses of intraperitoneal administration of rat nephrotoxic serum (NTS) preceded by IgG sensitization, in 7 weeks old male 129/Sv mice. The treatment group received GQ-16 (40 mg/kg) daily by oral gavage, while the control group received vehicle (n=4) for 7 days. Albuminuria and Transdermal Glomerular Filtration Rate (GFR) was measured serially, and kidneys and glomeruli were harvested at the end of the study for analyses. Results: Robust albuminuria was observed with NTS injury on Day 3 (73.4 ±33.2 mg/mg vs Control 0.22±0.06 mg/mg), which was significantly decreased up to 80% with GQ-16 treatment (p=0.0025). On Day 7, NTS injured group showed a reduction in GFR, whereas no differences were observed in GFR in the GQ-16 treatment group compared to baseline. Histopathological examination demonstrated segmental sclerosis, hyalinosis, and hypercellularity in Bowman’s space in the NTS group (17.7% ± 4.3 glomeruli affected), tubular protein casts (90% ± 2.8) and interstitial inflammation (13% ± 6.0). These pathological findings were not observed in the GQ-16 treatment group. There were no changes in the weight among the groups. Additionally, gene expression of podocyte markers, nephrin, podocin, and WT1 was increased in GQ-16 group treatment compared with the NTS injury group. Conclusion: Together, our findings suggest that GQ-16 might be an attractive and promising pharmacological intervention for treating RPGN. Funding: NIDDK Support