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Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: A novel mechanism of albumin-induced tubulointerstitial inflammation

Author:
Liu, Dan, Xu, Min, Ding, Li-Hong, Lv, Lin-Li, Liu, Hong, Ma, Kun-Ling, Zhang, Ai-Hua, Crowley, Steven D., Liu, Bi-Cheng
Source:
The international journal of biochemistry & cell biology 2014 v.57 pp. 7-19
ISSN:
1357-2725
Subject:
acetylcysteine, albumins, albuminuria, animal models, atrophy, biopsy, caspase-1, epithelial cells, genes, immunoglobulin A, inflammasomes, inflammation, interleukin-18, interleukin-1beta, kidney diseases, kidneys, mitochondria, patients, rats, reactive oxygen species
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.
Agid:
6016397