NADPH Oxidase-Mediated Triggering of Inflammasome Activation in Mouse Podocytes and Glomeruli During Hyperhomocysteinemia
- 1 May 2013
- journal article
- research article
- Published by Mary Ann Liebert Inc in Antioxidants and Redox Signaling
- Vol. 18 (13), 1537-1548
- https://doi.org/10.1089/ars.2012.4666
Abstract
Aim: Our previous studies have shown that NOD-like receptor protein (NALP3) inflammasome activation is importantly involved in podocyte dysfunction and glomerular sclerosis induced by hyperhomocysteinemia (hHcys). The present study was designed to test whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated redox signaling contributes to homocysteine (Hcys)-induced activation of NALP3 inflammasomes, an intracellular inflammatory machinery in podocytes in vitro and in vivo. Results: In vitro confocal microscopy and size-exclusion chromatography revealed that upon NADPH oxidase inhibition by gp91phox siRNA, gp91ds-tat peptide, diphenyleneiodonium, or apocynin, aggregation of inflammasome proteins NALP3, apoptosis-associated speck-like protein (ASC), and caspase-1 was significantly attenuated in mouse podocytes. This NADPH oxidase inhibition also resulted in diminished Hcys-induced inflammasome activation, evidenced by reduced caspase-1 activity and interleukin-1β production. Similar findings were observed in vivo where gp91phox−/− mice and mice receiving a gp91ds-tat treatment exhibited markedly reduced inflammasome formation and activation. Further, in vivo NADPH oxidase inhibition protected the glomeruli and podocytes from hHcys-induced injury as shown by attenuated proteinuria, albuminuria, and glomerular sclerotic changes. This might be attributed to the fact that gp91phox−/− and gp91ds-tat-treated mice had abolished infiltration of macrophages and T-cells into the glomeruli during hHcys. Innovation: Our study for the first time links NADPH oxidase to the formation and activation of NALP3 inflammasomes in podocytes. Conclusion: Hcys-induced NADPH oxidase activation is importantly involved in the switching on of NALP3 inflammasomes within podocytes, which leads to the downstream recruitment of immune cells, ultimately resulting in glomerular injury and sclerosis. Antioxid. Redox Signal. 18, 1537–1548.Keywords
This publication has 38 references indexed in Scilit:
- Cystathionine β-synthase and cystathionine γ-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generationAmerican Journal of Physiology-Cell Physiology, 2011
- Functional consequences of the collagen/elastin switch in vascular remodeling in hyperhomocysteinemic wild-type, eNOS−/−, and iNOS−/− miceAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
- The missing link: how the inflammasome senses oxidative stressImmunology & Cell Biology, 2010
- Redox signaling via lipid raft clustering in homocysteine-induced injury of podocytesBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2010
- Protection of podocytes from hyperhomocysteinemia-induced injury by deletion of the gp91phox geneFree Radical Biology & Medicine, 2010
- Contribution of Guanine Nucleotide Exchange Factor Vav2 to Hyperhomocysteinemic Glomerulosclerosis in RatsHypertension, 2009
- Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and SilicaScience, 2008
- α 2 -Adrenoceptors Enhance Angiotensin II–Induced Renal VasoconstrictionHypertension, 2008
- Mechanisms of Homocysteine-Induced Glomerular Injury and SclerosisAmerican Journal of Nephrology, 2007
- Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathwayFEBS Letters, 2007