Thioredoxin‐Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

Abstract

Kidney in diabetic state is more sensitive to ischemic acute kidney injury (AKI). However, the underlying mechanisms remain unclear. Herein, we examined the impact of diabetes mellitus on thioredoxin-interacting protein (TXNIP) expression and whether mediated NLRP3 activation was associated with renal ischemia/reperfusion- (I/R-) induced AKI. In an in vivo model, streptozotocin-induced diabetic rats showed higher susceptibility to I/R injury with increased TXNIP expression, which was significantly attenuated by resveratrol (RES) treatment (10 mg/kg intraperitoneal daily injection for 7 consecutive days prior to I/R induction). RES treatment significantly inhibited TXNIP binding to NLRP3 in diabetic rats subjected to renal I/R injury. Furthermore, RES treatment significantly reduced cleaved caspase-1 expression and production of IL-1β and IL-18. In an in vitro study using cultured human kidney proximal tubular cell (HK-2 cells) in high glucose condition (HG, 30 mM) subjected to hypoxia/reoxygenation (H/R), HG combined H/R (HH/R) stimulated TXNIP expression which was accompanied by increased NLRP3 expression, ROS generation, caspase-1 activity and IL-1β levels, and aggravated HK-2 cells apoptosis. All these changes were significantly attenuated by TXNIP RNAi and RES treatment. In conclusion, our results demonstrate that TXNIP-mediated NLRP3 activation through oxidative stress is a key signaling mechanism in the susceptibility to AKI in diabetic models.

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

“…Tang et al [23] reported that downregulation of NLRP3 inflammasome activation protects the kidney against ischaemia/reperfusion injury. Additionally, Xiao et al [12] demonstrated that NLRP3 activation mediated by oxidative stress plays an important role in susceptibility to AKI in diabetes models. Studies have also shown that the NLRP3 inflammasome contributes to sepsis [32,33].…”

“…The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is an important component of the innate immune system, as it initiates early inflammatory responses by inducing caspase-1 activation and IL-1β maturation [10,11]. The NLRP3 inflammasome plays a role in the pathogenesis of renal diseases, including AKI [12]. One study showed that knockout of the NLRP3 inflammasome protected mice against ischaemia-induced AKI [13].…”

Viroporins and inflammasomes: A key to understand virus-induced inflammation

“…The source of ROS is under debate where some studies claim one or several NADPH oxidases to be involved, while others support mitochondrial origin [76]. A recent report associates a ROS-sensitive NLRP3 ligand, thioredoxin-interacting protein (TXNIP/VDUP1), in NLRP3 activation [77].…”

Renoprotective effects Of Dexmedetomidine against ischemia-reperfusion injury in streptozotocin-induced diabetic rats

“…[24] Previously, TXNIP-mediated NLRP3 activation via oxidative stress was identified as a key signaling mechanism in susceptibility to AKI. [16,25] DEX administered to diabetic rats ameliorates lipid peroxidation, oxidative stress, and IRrelated renal injury partly by inhibiting P38-MAPK (mitogen-activated protein kinases) activation and expression of TXNIP in diabetic kidney. [7,26] In this study, DEX treatment, especially post-treatment, attenuated increase in oxidative stress markers (CTP1A, NOX4, and TXNIP) following IR.…”