H2S treatment improves protective effect of MSC-derived exosomes upon of renal ischemia/reperfusion fibrosis by suppressing inflammatory signaling of TGF-β and NF-kB as well as ROS generation

Abstract

IntroductionH2S has been reported to participate in renal I/R fibrosis-associated signaling pathways. In this study, the authors hypothesized that the preconditioning with H2S could boost the effect of exosomes in the therapy of renal I/R fibrosis.Material and methodsReal-time PCR and Western blot was performed to analyze the gene and protein expression of Nrf2, NF-κB, TGF-β, α-SMA, and Col2 (Collagen Type II) in distinct conditions. H&E and MASSON staining were carried out to examine the kidney injury and fibrosis in I/R rats.ResultsH2S-preconditioned EXOs remarkably reinforced the therapeutic role of EXOs on attenuating the kidney injury in I/R rats. EXOs treatment significantly restored the activated gene and protein expression of NF-κB, TGF-β, α-SMA, and Col2 in I/R rats and cellular models, while H2S preconditioning remarkably strengthened the efficiency of EXOs. Besides, H2S preconditioning remarkably strengthened the efficiency of EXOs in restoring the activated expression of IL-1α, IL-6, IL-12 and TNF-α in I/R rats and cellular models and maintaining the altered activities of SOD, MDA, H2O2, GST and GPx.ConclusionsThis study utilized I/R rats to demonstrate that the administration of H2S- preconditioned exosomes showed more significant effect in inflammation and ROS generation than the unconditioned exosomes. To be specific, exosomes, especially H2S- preconditioned exosomes, could not only reduce the expression of NF-κB and the downstream inflammatory responses, but also promote the expression of Nrf2 and regulate ROS generation, leading to potential therapeutic effect on renal I/R fibrosis.