Immortalized Human Kidney Podocytes-SV40

Unfolded Protein Response-Activated NLRP3 Inflammasome Contributes To Pyroptotic and Apoptotic Podocyte Injury in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Podocyte injury and death is a key event in DKD progression. Emerging evidence has indicated that crosstalk between unfolded protein response (UPR) and NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an essential role in DKD progression. However, the involvement of these pathways in podocyte injury and death during DKD remains unclear.

Here, we found that inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) branches of the UPR, NLRP3 inflammasome, and apoptosis were activated in podocytes under DKD and high glucose (HG) conditions. In vitro, inducing ER stress by thapsigargin, and IRE1 or PERK overexpression upon HG treatment stimulated NLRP3 inflammasome-mediated pyroptosis and apoptosis, whereas inhibiting IRE1 or PERK suppressed them. Importantly, we discovered that the newly identified NLRP3-binding partner, thioredoxin-interacting protein (TXNIP), upon activation by the transcription factor (TF) PERK/CCAAT-enhancer-binding protein homologous protein (CHOP), served as a link between IRE1 or PERK branches with NLRP3 inflammasome-mediated pyroptosis and apoptosis.

In conclusion, the results suggested that UPR/NLRP3 inflammasome-mediated pyroptosis/apoptosis pathway was involved in diabetic podocyte injury, and that targeting the CHOP-TXNIP axis may serve as a promising therapeutic target for DKD.