The protective effect and molecular mechanism of glycyrrhizic acid glycosides against Tripterygium glycosides induced nephrotoxicity based on the RhoA/ROCK1 signalling pathway

Tripterygium glycosides (TG), which are extracted from the traditional Chinese medicine, Tripterygium wilfordii Hook F. (TwHF), has promising applications in the treatment of renal diseases; however, since its active components exerts bidirectional kidney toxicity, its clinical application is severely restricted.Recent investigations have demonstrated definite toxicity-reducing effects from glycyrrhizic acid glycosides (GA) when combined with TG; however, the mechanism remains unclear. To our knowledge, this is the first study to investigate the specific molecular mechanism by which GA alleviates TG-induced renal toxicity from the perspective of tight junctions.Dynamic analyses, which investigated the changes in kidney toxicity biomarkers for different combinations and concentrations of TG and GA, were conducted for three weeks on SD rats and renal tissue structural changes were examined after three weeks of administration. Additionally, the transcription and translation levels of the relevant tight junctions and RhoA/ROCK1/MLC signalling proteins were analysed in HK-2 cells.Our study showed that TG can cause transient tubulotoxicity at certain doses, and that the combined application of GA and TG can repair tight junction structures by regulating the key factors in the RhoA/ROCK1/MLC signalling pathway, thus reducing TG-induced nephrotoxicity.Overall, this study provides a new strategy to reduce TG-induced toxicity by protecting renal tight junctions.