GS-4997 halts the progression of tubulointerstitial injury in lupus nephritis

Tubulointerstitial injury has been increasingly recognized as an important component in lupus nephritis (LN) pathology over the last decades. However, current clinical treatment options for this process remain limited. In this study, we aimed to investigate the potential benefits of GS-4997, a selective inhibitor of ASK1, in tubulointerstitial injury of LN. Female MRL/lpr mice were used as a classical lupus-prone murine model. Development of nephritis was assessed by monitoring of proteinuria, renal function, and histologic analysis. GS-4997 (50 mg/kg) or vehicle were treated orally. In vitro study, human kidney-2 (HK-2) cells were stimulated with 1 μg/mL lipopolysaccharide (LPS) to mimic the response of renal tubular epithelial cells undergoing inflammatory responses during LN. GS-4997 could inhibit the activation of the ASK1 in renal tubulointerstitium in MRL/lpr mice and LPS-induced HK-2 cells. GS-4997 treatment improved renal function, proteinuria, and attenuated tubular injury, renal interstitial fibrosis, and inflammation both in vivo and in vitro. Additionally, we found that in MRL/lpr mice, GS-4997 reduced deposition of IgG and C3 in the kidneys, antibody levels in the serum, splenic enlargement, and inflammatory cell infiltration in the spleen. Mechanistically, GS-4997 inhibited the activation of downstream signaling molecules, p38 and JNK, in the ASK1 signaling pathway. Pharmacological inhibition of ASK1 may prevent the progression of tubulointerstitial injury via inhibiting the ASK1/MAPK pathway in LN. Therefore, our findings demonstrate the potential use of GS-4997 for LN treatment.