Thioredoxin Interacting Protein Deficiency Protects Against Obesity‐Induced Podocyte Injury and Glomerular Sclerosis

Abstract

Recently we have shown that activation and formation of NLRP3 inflammasomes in podocytes is implicated in the development of obesity‐induced glomerular injury. Moreover, we demonstrated that NADPH oxidase dependent O2•− production (ROS) mediates the obesity‐induced NLRP3 inflammasomes activation and thereby results in podocyte injury and glomerular damage. However, it remains unknown how NADPH oxidase‐derived ROS is sensed by NLRP3 inflammasomes in podocytes upon visfatin stimulation. The current study tested whether thioredoxin‐interacting protein (TXNIP) mediates obesity‐induced NLRP3 inflammasome activation and consequent glomerular injury. In cultured podocytes, confocal microscopic analysis showed that visfatin treatment significantly increased the colocalization of NLRP3 with Asc or caspase‐1 in podocytes compared to control cells. Pretreatment with TXNIP siRNA abolished the visfatin‐induced inflammasome formation. Correspondingly, visfatin treatment significantly increased the caspase‐1 activity and IL‐1β production compared to control cells. The TXNIP siRNA transfection significantly attenuated the visfatin‐induced caspase‐1 activity and IL‐1β production. Further immunofluorescence analysis showed that visfatin treatment significantly decreased the podocin expression (podocyte damage) compared to control cells. However, pretreatment with TXNIP siRNA attenuated the visfatin‐induced podocin reduction. In in vivo studies, adult C57BL/6J male mice were fed a high fat diet for 14 weeks to induce obesity, and TXNIP was inhibited by verapamil (1 mg/ml in drinking water). High fat diet significantly increased the plasma visfatin levels compared to control mice. In addition, RT‐PCR analysis showed that high fat diet significantly increased the Nlrp3 expression in glomeruli of wild type mice compared to control mice but not in verapamil treated mice. Furthermore, TXNIP inhibition significantly reduced IL‐1β production in glomeruli of mice with obesity. Correspondingly, TXNIP inhibitor, verapamil attenuated obesity‐induced proteinuria, glomerular damage and podocyte injury. In conclusion, our results demonstrate that TXNIP binding to NLRP3 is a key signaling mechanism necessary for obesity‐induced NLRP3 inflammasome formation and activation and subsequent glomerular injurySupport or Funding InformationNIH grant, DK104031This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.