Abstract
Our previous studies have shown the importance of NADPH oxidase‐derived reactive oxygen species (ROS) in hyperhomocysteinemia (hHcys)‐induced glomerular injury. Using SOD mimetic TEMPOL, catalase, and uric acid to reduce superoxide (O2•−), hydrogen peroxide (H2O2), and peroxynitrite (ONOO−), we have recently shown that these ROS are involved in hHcys‐induced inflammasome activation in podocytes. The present study was designed to further test whether in vivo scavenging of O2•−and H2O2 attenuates NLRP3 inflammasome activation and glomerular injury in mice with hHcys. Uninephrectomized C57BL/6J wild type mice were fed either normal chow (ND) or a folate free (FF) diet for 4 weeks to produce hHcys. Confocal microscopy showed that hHcys increased the colocalization of inflammasome proteins NLRP3 with ASC or caspase‐1 in the glomeruli compared to ND fed mice. Inflammasome formation mainly occurred in podocytes as shown by colocalization of NLRP3 with podocyte marker podocin. In vivo scavenging of O2•− by TEMPOL and removal of H2O2 by catalase substantially inhibited NLRP3 inflammasome formation in glomeruli of hHcys mice. Correspondingly, TEMPOL and catalase treatment inhibited hHcys‐induced caspase‐1 activation, respectively by 25.9% and 33.8%, and decreased IL‐1β production by 38.8% and 35.7%. ESR analysis demonstrated that TEMPOL produced a 44.3% decrease of renal O2•−production, while catalase produced a 42.4% decrease. Importantly, reduction of both O2•−and H2O2 was found to protect glomerular function and structure, preventing hHcys‐induced proteinuria, albuminuria and glomerular morphological pathology. Together, these results indicate that endogenously produced O2•− and H2O2 contribute to NLRP3 inflammasome formation and activation in vivo at early stage hHcys and that inhibition of these ROS may prevent NLRP3 inflammasome activation and subsequent glomerular injury (supported by NIH grants DK54927 and 1F31AG043289).
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