Calcium-binding proteins annexin A2 and S100A6 are sensors of tubular injury and recovery in acute renal failure.
BACKGROUND
Rise in cellular calcium is associated with acute tubular necrosis, the most common cause of acute renal failure (ARF). The mechanisms that calcium signaling induce in the quiescent tubular cells to proliferate and differentiate during acute tubular necrosis have not been elucidated.


METHODS
Acute tubular necrosis induced in mice by single intravenous injection of uranyl nitrate and examined after 1, 3, 7, and 14 days. Renal function was monitored and kidneys were evaluated by histology, immunohistochemistry, Western blotting, in situ hybridization, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Models of folic acid induced-ARF and ischemic/reperfusion (I/R) injury were similarly investigated.


RESULTS
Analysis of mRNA expression of intracellular calcium and phospholipid-binding proteins demonstrated selective expression of S100A6 and Annexin A2 (Anxa2) in the renal cortex with marked elevation on day 3, and gradually decline on day 7 and further attenuation on day 14. Similarly, the expression of both proteins, as demonstrated by immunohistochemistry and Western blot analysis, was increased and reached the peak level on day 7 and then gradually declined by day 14. Vimentin, a marker of dedifferentiated cells, was highly expressed during the recovery phase. Combined in situ hybridization immunohistochemistry revealed colocalization of both S100A6 and Anxa2 with proliferating cell nuclear antigen (PCNA). The universality of this phenomenon was confirmed in two other mouse acute tubular necrosis models, the ischemic-reperfusion injury and folic acid-induced ARF.


CONCLUSIONS
Collectively, these findings demonstrate that S100A6 and Anxa2 expression, initiated in response to tubular injury, persist in parallel throughout the recovery process of tubular cells in acute renal failure.
Cheng
Chao-Wen
CW
Graduate Institute of Life Sciences, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taiwan, Republic of China.
Rifai
Abdalla
A
Ka
Shuk-Man
SM
Shui
Hao-Ai
HA
Lin
Yuh-Feng
YF
Lee
Wei-Hwa
WH
Chen
Ann
A
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D005260:Female; D005492:Folic Acid / Q000633:toxicity; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D014502:Uranyl Nitrate / Q000633:toxicity; D014803:Vitamin B Complex / Q000633:toxicity
D017306:Annexin A2; D015415:Biomarkers; C111922:Cacybp protein, mouse; D002135:Calcium-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D014502:Uranyl Nitrate; D014803:Vitamin B Complex; D005492:Folic Acid