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Kidney Week

Abstract: TH-PO120

Novel Imaging Technique Visualizing Spatiotemporal ATP Dynamics During AKI Predicts Renal Prognosis and Provides Proof-of-Concept for Hypothermia

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Yamamoto, Shigenori, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Yamamoto, Shinya, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Yamamoto, Masamichi, Kyoto University Graduate School of Medicine, Kyoto, Japan
Background

The kidney constantly utilizes adenosine 5’ triphosphate (ATP), and mitochondrial dysfunction, which leads to ATP depletion, plays an important role in the pathogenesis of kidney diseases. In spite of importance of ATP dynamics, however, lack of technology to visualize in vivo ATP dynamics has hindered further analysis. Here we enabled the visualization of spatiotemporal renal ATP dynamics and analyzed whether the ATP dynamics during AKI could predict the renal prognosis.

Methods

To enable intravital ATP imaging, we generated a novel mouse line, which expressed the FRET-based ATP biosensor systemically. We monitored renal ATP dynamics in both warm and cold ischemic reperfusion (IR) models with two-photon microscope. Furthermore, we performed the quantification of fibrosis two weeks after IR, and assessed the correlation between the ATP recovery in acute phase and fibrosis in chronic phase.

Results

The ATP level of proximal tubules (PTs) rapidly decreased to the basal level in only 2 minutes after ischemia induction, whereas that of distal tubules (DTs) was maintained even after 30 minutes.
The ATP dynamics in PTs after reperfusion was variable depending on the duration of ischemic time. The longer ischemic time led to slower and more insufficient ATP recovery in PTs. The ATP recovery after 15, 30, and 60 minute-warm IR took 2, 5, and 30 minutes to reach a peak plateau, and the % ATP recovery were 90%, 83%, and 69%, respectively, while the ATP recovery after 30 and 60 minute-cold IR took 2 and 4 minutes, and the % ATP recovery were 90% and 87%, indicating rapid and complete ATP recovery in cold ischemia. Interestingly, the fibrosis in chronic phase was inversely well correlated with the ATP recovery of PTs in acute phase in both warm and cold IR.

Conclusion

We, for the first time, succeeded in visualizing the spatiotemporal ATP dynamics in the kidney and revealed the tolerance of DTs to ischemia from the point of ATP dynamics. After reperfusion, the ATP recovery in PTs was variable depending on the severity of injury, and the ATP dynamics in acute phase might determine the outcome in chronic phase. In addition, cold ischemia results in much more rapid and complete ATP recovery than warm ischemia, which provides proof of concept for renal hypothermia.