Journal of Biological Chemistry
Volume 289, Issue 36, 5 September 2014, Pages 25101-25111
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Molecular Bases of Disease
NLRP3 Inflammasome Mediates Albumin-induced Renal Tubular Injury through Impaired Mitochondrial Function*

https://doi.org/10.1074/jbc.M114.578260Get rights and content
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Proteinuria serves as a direct causative factor of renal tubular cell injury and is highly associated with the progression of chronic kidney disease via uncertain mechanisms. Recently, evidence demonstrated that both NLRP3 inflammasome and mitochondria are involved in the chronic kidney disease progression. The present study was undertaken to examine the role of NLRP3 inflammasome/mitochondria axis in albumin-induced renal tubular injury. In patients with proteinuria, NLRP3 was significantly up-regulated in tubular epithelial cells and was positively correlated with the severity of proteinuria. In agreement with these results, albumin remarkably activated NLRP3 inflammasome in both in vitro renal tubular cells and in vivo kidneys in parallel with significant epithelial cell phenotypic alteration and cell apoptosis. Genetic disruption of NLRP3 inflammasome remarkably attenuated albumin-induced cell apoptosis and phenotypic changes under both in vitro and in vivo conditions. In addition, albumin treatment resulted in a significant mitochondrial abnormality as evidenced by the impaired function and morphology, which was markedly reversed by invalidation of NLRP3/caspase-1 signaling pathway. Interestingly, protection of mitochondria function by Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) or cyclosporin A (CsA) robustly attenuated albumin-induced injury in mouse proximal tubular cells. Collectively, these findings demonstrated a pathogenic role of NLRP3 inflammasome/caspase-1/mitochondria axis in mediating albumin-induced renal tubular injury. The discovery of this novel axis provides some potential targets for the treatment of proteinuria-associated renal injury.

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*

This work was supported by National Basic Research Program of China 973 Program Grants 2012CB517602 and 2013CB530604; National Natural Science Foundation of China Grants 81325004, 81270797, and 81170635; Natural Science Foundation of Jiangsu Province Grant BK2012001, and Program for New Century Excellent Talents in University Grant NCET-12-0738.

2

The abbreviations used are:

    ROS

    reactive oxygen species

    CKD

    chronic kidney disease

    mPTC

    mouse proximal tubular cell

    mtDNA

    mitochondrial DNA

    MMP

    mitochondrial membrane potential

    qRT-PCR

    quantitative real time PCR

    TUNEL

    transferase dUTP nick end labeling

    MnTBAP

    Mn(III)tetrakis (4-benzoic acid) porphyrin

    CsA

    cyclosporin A

    Cyt C

    cytochrome C

    α-SMA

    α-smooth muscle actin.