Urinary ATP Synthase Subunit beta Is a Novel Biomarker of Renal Mitochondrial Dysfunction in Acute Kidney Injury

作者：Whitaker Ryan M; Korrapati Midhun C; Stallons Lindsey J; Jesinkey Sean R; Arthur John M; Beeson Craig C; Zhong Zhi; Schnellmann Rick G^*

来源：Toxicological Sciences, 2015, 145(1): 108-117.

DOI：10.1093/toxsci/kfv038

• acute kidney injury
• ischemia-reperfusion
• mitochondria
• biomarker
• ATP synthase beta

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 beta (ATPS beta) 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 ATPS beta revealed two bands (full length similar to 52 kDa and cleaved similar to 25 kDa), both confirmed as ATPS beta 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, ATPS beta and COX1, proximal tubular oxygen consumption, and ATP. Furthermore, in the 15-min I/R group, urinary ATPS beta was elevated until 72 h before returning to baseline 144 h after reperfusion with recovery of renal function. Evaluation of urinary ATPS beta in a nonalcoholic steatohepatitis model of liver injury only revealed cleaved ATPS beta, suggesting specificity of full-length ATPS beta for renal injury. Immunoblot analyses of patient urine samples collected 36 h after cardiac surgery revealed increased urinary ATPS beta levels in patients with postcardiac surgery-induced AKI. LC-MS/MS urinalysis in human subjects with AKI confirmed increased ATPS beta. These translational studies provide evidence that ATPS beta 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.

• 出版日期2015-5