Triptolide protects against podocyte injury in diabetic nephropathy by activating the Nrf2/HO-1 pathway and inhibiting the NLRP3 inflammasome pathway

Abstract

Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN. Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2. Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells. Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.

Transcriptome analysis reveals the mechanism of pyroptosis-related genes in septic cardiomyopathy

“…To detect cell pyroptosis ( Shi et al, 2021 ; He et al, 2020 ; Lv et al, 2023 ), Hoechst 33342/PI staining was used on LPS-induced cells and control cells. The cells were seeded in six-well plates at a density of 2 × 10 5 cells per well and cultured for 24 h of incubation.…”

Triptolide decreases podocytes permeability by regulating TET2-mediated hydroxymethylation of ZO-1

“…Currently, there are conflicting reports on the toxicity and therapeutic effects of TP on the kidney [10,27,28]. TP showed renoprotection effects against metronidazole-induced injury in zebrafish, puromycin-induced nephropathy, PM 2.5-induced podocyte injury, and deoxycorticosterone acetate-salt hypertension-induced renal injury in mice subjected to uninephrectomy [13,29,30]. In contrast, TP was also shown to exert nephrotoxicity in normal BALB/c mice and renal tubular epithelial cell lines NRK-52E and HK-2 [31][32][33].…”

Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications

“…asserted that the mitigation of high glucose (HG)-induced pyroptosis in Madin-Darby canine kidney (MDCK) cells can be achieved by reducing the expression levels of NLRP3 and GSDMD ( 62 ). Moreover, the inhibition of pyroptosis by mediating NLRP3 inflammasome pathways can alleviate podocyte pyroptosis ( 63 – 65 ). As researchers continue to explore this field, the up-regulation of Toll-like receptor 4 (TLR4) and GSDMD coincides with the tubular injury observed in DN patients.…”