Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 308, Issue 8, Pages F857-F866Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00203.2014
Keywords
mitochondria; NOD-like receptor family; pyrin; domain-containing 3; proteinuria; renal tubular injury
Categories
Funding
- National Basic Research Program of China 973 Program [2012CB517602]
- National Natural Science Foundation of China [81270785, 81325004, 81470928]
- Natural Science Foundation of Jiangsu Province [BK2012001]
- Jiangsu Provincial Special Program of Medical Science [BL2014007]
Ask authors/readers for more resources
Proteinuria is involved in the development of tubular lesions and in the progressive loss of renal function in chronic kidney diseases via uncertain mechanisms. Growing evidence suggests a pathogenic role of mitochondrial dysfunction in chronic kidney diseases. Therefore, the present study aimed to define the roles of mitochondria in proteinuria-induced renal tubular injury and their underlying mechanisms. Using the albumin-overload mouse model, we observed severe tubular structure damage and striking tubular cell apoptosis. Furthermore, tubular epithelial cells displayed a loss of E-cadherin expression and gained expression of alpha-smooth muscle actin and vimentin, indicating a cellular phenotypic alteration. Strikingly, these albumin overload-induced abnormalities were robustly blocked by a mitochondrial SOD2 mimic, Mn(III) tetrakis (4-benzoic acid)porphyrin chloride (MnTBAP). In agreement with these results, we observed a marked change in mitochondrial morphology accompanied by mitochondrial cytochrome c release and a copy number reduction of mitochondrial DNA. These alterations were largely reversed by MnTBAP, suggesting a key role for mitochondria-derived oxidative stress in mediating the albumin effect on mitochondrial dysfunction and subsequent tubular injury. Moreover, the NOD-like receptor family, pyrin domain-containing 3 (NLRP3)/caspase-1/cytokine cascade was activated in the kidney by albumin overload and was entirely abolished by MnTBAP. In albumin-treated mouse proximal tubular cells, albumin directly induced ROS production, mitochondrial dysfunction, NLRP3/caspase-1/cytokine cascade activation, cell apoptosis, and cellular phenotypic transition. Similar to our in vivo results, treatment with either MnTBAP or cyclosporin A, a mitochondrial permeability transition pore inhibitor, remarkably attenuated these abnormalities in cells. Taken together, these novel findings demonstrate a potential role for the mitochondrial dysfunction/NLRP3 inflammasome axis in the pathogenesis of proteinuria-induced renal tubular injury.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available