JPH203 alleviates renal fibrosis via inhibition of serine-related mTORC1 pathway in TGF-β1-induced fibroblasts and UUO mice

Renal fibrosis is the common pathological outcome of chronic kidney disease (CKD) progressing into end-stage renal disease. The excessive proliferation of fibroblasts plays an important role in the CKD progression. Nutrients such as Amino acids and their transportation are essential for cell proliferation. In this study, TGF-β1-induced fibroblasts and UUO mouse models were used. The target gene solute carrier family 7 member 5 (SLC7A5) was screened to be highly expressed and localized in the renal fibroblasts of CKD mice. In vivo experiments showed that SLC7A5 promoted the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, enhanced serine synthesis and maintained oxidative stress balance in fibroblasts. SLC7A5 increased the expression of transcription factor activating transcription factor 4 (ATF4), promoted the transcription of serine de-novo synthesis enzyme PHGDH, and increased the synthesis of glutathione, a byproduct of serine synthesis pathway. JPH203, a specific inhibitor of SLC7A5, effectively reversed the above phenomena, inhibited mTORC1 signaling activation, and reduced the proliferation of fibroblasts. The efficacy of JPH203 was further verified by in vivo experiments. JPH203 had a similar effect to the inhibitory adenovirus AV-shSLC7A5 in the UUO mouse model. Compared with the UUO group, the activation of mTORC1 pathway in the JPH203 treatment group was inhibited, and the expressions of α-SMA and vimentin in fibroblasts were decreased. The fibrotic state of renal tissues was effectively relieved. In addition, the levels of serum creatinine, blood urea nitrogen and pelvic urinary protein were significantly decreased compared with the UUO group. In conclusion, our study demonstrated that JPH203 can alleviate renal fibrosis via inhibition of serine-related mTORC1 pathway in fibroblasts in UUO mice. These results may provide a theoretical foundation for the pathogenesis of renal fibrosis and a novel therapeutic strategy for CKD.

Chronic kidney disease; Fibroblast; JPH203; Mammalian target of rapamycin complex 1; Renal fibrosis; Solute carrier family 7 member 5.