Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: A novel mechanism of albumin-induced tubulointerstitial inflammation |
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| Affiliation: | 1. Department of Forest and Wildlife Ecology, University of Wisconsin-Madison, Madison, WI 53706, USA;2. Departamento de Bioquímica y Ciencias Biológicas y Laboratorio de Biología “Profesor E. Caviedes Codelia”, Universidad Nacional de San Luis, 5700 San Luis, Argentina;3. Laboratorio de Biología Integrativa, Instituto Multidisciplinario de Investigaciones Biológicas de San Luis, Consejo Nacional de Investigaciones Científicas y Técnicas, 5700 San Luis, Argentina;1. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;2. Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;3. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia;4. College of Pharmacy, Al Ain University, Abu Dhabi 112612, United Arab Emirates;5. Deanship of Scientific Research, King Abdulaziz University, Jeddah, Saudi Arabia;6. Department of Entomology, Rutgers University, New Brunswick, NJ 08901, USA;7. Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia;8. College of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro, Yeonsu-gu, Incheon City 21924, South Korea |
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| Abstract: | Albuminuria is not only an important marker of chronic kidney disease but also a crucial contributor to tubulointerstitial inflammation (TIF). In this study, we determined whether activation of the Nlrp3 inflammasome is involved in albuminuria induced-TIF and the underlying mechanisms of inflammasome activation by mitochondrial reactive oxygen species (mROS). We established an albumin-overload induced rat nephropathy model characterised by albuminuria, renal infiltration of inflammatory cells, tubular dilation and atrophy. The renal expression levels of the Nlrp3 inflammasome, IL-1β and IL-18 were significantly increased in this animal model. In vitro, albumin time- and dose-dependently increased the expression levels of the Nlrp3 inflammasome, IL-1β and IL18. Moreover, the silencing of the Nlrp3 gene or the use of the caspase-1 inhibitor Z-VAD-fmk significantly attenuated the albumin-induced increase in IL-1β and IL-18 expression in HK2 cells. In addition, mROS generation was elevated by albumin stimulation, whereas the ROS scavenger N-acetyl-l-cysteine (NAC) inhibited Nlrp3 expression and the release of IL-1β and IL-18. In kidney biopsy specimens obtained from patients with IgA nephropathy, Nlrp3 expression was localised to the proximal tubular epithelial cells, and this result is closely correlated with the extent of proteinuria and TIF. In summary, this study demonstrates that albuminuria may serve as an endogenous danger-associated molecular pattern (DAMP) that stimulates TIF via the mROS-mediated activation of the cytoplasmic Nlrp3 inflammasome. |
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| Keywords: | Nlrp3 inflammasome Albuminuria Mitochondrial reactive oxygen species Proximal tubular epithelial cell Tubulointerstitial inflammation |
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