Urinary ATP synthase subunit β is a novel biomarker of renal mitochondrial dysfunction in acute kidney injury

Ryan M. Whitaker, Midhun C. Korrapati, Lindsey J. Stallons, Sean R. Jesinkey, John M. Arthur, Craig C. Beeson, Zhi Zhong, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Although 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 15min ischemia) of ischemia/reperfusion (I/R)-induced AKI. Serum creatinine, BUN, and neutrophil gelatinase-associated lipocalin were elevated only in the 15min 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 24h 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 72h before returning to baseline 144h 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 36h 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.

Original languageEnglish (US)
Pages (from-to)108-117
Number of pages10
JournalToxicological Sciences
Volume145
Issue number1
DOIs
StatePublished - May 1 2015
Externally publishedYes

Keywords

  • Acute kidney injury
  • ATP synthase β
  • Biomarker
  • Ischemia-reperfusion
  • Mitochondria

ASJC Scopus subject areas

  • Toxicology

Fingerprint

Dive into the research topics of 'Urinary ATP synthase subunit β is a novel biomarker of renal mitochondrial dysfunction in acute kidney injury'. Together they form a unique fingerprint.

Cite this