PDIA4 Ameliorates Renal Tubular Pyroptosis via Suppressing IRE1a-sXBP1 Pathway in Diabetic Kidney Disease
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Wang, Dekun, Nankai University, Tianjin, Tianjin, China
- Liu, Xuan, Nankai University, Tianjin, Tianjin, China
- Tan, Xiaoyue, Nankai University, Tianjin, Tianjin, China
Accumulating evidences imply the vital role of tubular injury in the pathogenesis of DKD, as well as of ER stress, the regulatory machinery of protein homeostasis. ER stress results in the activation of distinct unfolded protein response (UPR), and the effect of conserved UPR branch IRE1 on the diabetic tubular injury is still elusive.
We evaluated the activation of IRE1a/sXBP1 and NLPR3 inflammasome, as well as pyroptosis in the high glucose-stressed tubular cells. Furthmore, effects and underlying mechanism of PDIA4 on the activation of IRE1a induced by high glucose were investigated.
We identified the activated IRE1α/sXBP1 and NLRP3 inflammasome, as well as pyroptosis via analyzing the differential genes expression in the diabetic tubules, which was further confirmed in the glucose-stressed tubular cells and biopsy samples from patients of DKD. Consistently, silencing down of IRE1α or administration of IRE1α inhibitor alleviates high glucose-induced NLRP3 inflammasome and pyroptosis. Furthermore, we revealed that PDIA4 suppresses the high glucose-induced tubular IRE1α/sXBP1. Immunoprecipitation and crosslinking assay demonstrated that high glucose promotes the dynamic interaction among PDIA4, Bip and IRE1α. That is, dissociation of Bip with IRE1α and Bip with PDIA4, while increase of PDIA4 with IRE1α. Bond of PDIA4 with IRE1α depends on -CHGC motif, and thus suppresses the activation of IRE1α/sXBP1. Dual-luciferase assay revealed that sXBP1 transcriptionally induces HSC70, hence results in the decrease of PDIA4 via CMA dependent degradation. In vivo, we overexpressed PDIA4 in two mouse models of DKD via injection of AAV9-PDIA4. Our data demonstrated the ectopic overexpression of PDIA4 alleviates the diabetic tubular injury and inflammation reaction, accompanied with the reduced IRE1α/sXBP1 and NLRP3 inflammasome.
Altogether, we revealed that the stress of high glucose activates IRE1α/sXBP1 pathway, NLRP3 inflammasome and pyroptosis in renal tubular cells. XBP1s reduces PDIA4 via induction of HSC70 and thus selective CMA degradation. Reciprocally, PDI4 exhibits inhibitory effect on IRE1α/sXBP1 pathway via bond with oligomerized IRE1α.
- Government Support – Non-U.S.