• Ryan M Whitaker, Midhun C Korrapati, Lindsey J Stallons, Sean R Jesinkey, John M Arthur, Craig C Beeson, Zhi Zhong, and Rick G Schnellmann.
• *Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, Department of Medicine, Division of Nephrology, Medical University of South Ca... more rolina, Charleston, South Carolina 29425 and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina 29425 schnell@musc.edu. less
• Toxicol. Sci. 2015 May 1; 145 (1): 108-17.

AbstractAlthough the importance of mitochondrial dysfunction in acute kidney injury (AKI) has been documented, noninvasive early biomarkers of mitochondrial damage are needed. We examined urinary ATP synthase subunit β (ATPSβ) as a biomarker of renal mitochondrial dysfunction during AKI. Mice underwent sham surgery or varying degrees (5, 10, or 15 min ischemia) of ischemia/reperfusion (I/R)-induced AKI. Serum creatinine, BUN, and neutrophil gelatinase-associated lipocalin were elevated only in the 15 min I/R group at 24 h. Immunoblot analysis of urinary ATPSβ revealed two bands (full length ∼52 kDa and cleaved ∼25 kDa), both confirmed as ATPSβ by LC-MS/MS, that increased at 24 h in 10- and 15-min I/R groups. These changes were associated with mitochondrial dysfunction evidenced by reduced renal cortical expression of mitochondrial proteins, ATPSβ and COX1, proximal tubular oxygen consumption, and ATP. Furthermore, in the 15-min I/R group, urinary ATPSβ was elevated until 72 h before returning to baseline 144 h after reperfusion with recovery of renal function. Evaluation of urinary ATPSβ in a nonalcoholic steatohepatitis model of liver injury only revealed cleaved ATPSβ, suggesting specificity of full-length ATPSβ for renal injury. Immunoblot analyses of patient urine samples collected 36 h after cardiac surgery revealed increased urinary ATPSβ levels in patients with postcardiac surgery-induced AKI. LC-MS/MS urinalysis in human subjects with AKI confirmed increased ATPSβ. These translational studies provide evidence that ATPSβ may be a novel and sensitive urinary biomarker of renal mitochondrial dysfunction and could serve as valuable tool for the testing of potential therapies for AKI and chemical-induced nephrotoxicity.Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

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