Celastrol modulates damage of renal tissues in Immunoglobulin A nephropathy via targeting TGase-2/HMGB1 signaling pathway

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BACKGROUND: Persistent controversies surround the treatment of Immunoglobulin A nephropathy (IgAN), necessitating the exploration of safer and more effective therapeutic agents. Tripterygium wilfordii, a traditional Chinese medicine, demonstrates promising benefits in reducing proteinuria and enhancing renal function in IgAN. This study aims to elucidate the therapeutic mechanisms of celastrol, a principal medicinal component of Tripterygium wilfordii, in IgAN treatment. METHODS: An IgAN rat model was induced using lipopolysaccharide, carbon tetrachloride, and bovine serum albumin. HMCs cells were stimulated by aIgA1 to establish IgAN model in vitro. Immunofluorescence, immunohistochemistry and HE staining were performed using renal tissues. Western Blot and RT-PCR were utilized to measure the protein and mRNA expressions of TGase-2, HMGB1, TLR4, and MYD88 in vivo and in vitro. RESULTS: Celastrol treatment exhibited reduced levels of proteinuria, diminished pathological kidney damage, and decreased expression of TGase-2 and HMGB1 in the renal tissue of IgAN rats. Furthermore, celastrol treatment or TGase-2 knockdown decreased the expression of TGase-2, HMGB1, TLR4, and MYD88 in both proteins and mRNA levels in, and the contents of HMGB1, TNF-α, IL-6, and FN in the in aIgA1 stimulated HMCs. CONCLUSION: Our study findings provide evidence supporting the efficacy of celastrol in treating IgAN. The potential underlying mechanisms involve the reduction of cell proliferation and inflammatory response by inhibiting the expression of the TGase-2/HMGB1 pathway.