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Experiments using a novel mouse strain that incorporates an ATP biosensor to visualize spatiotemporal ATP dynamics at single-cell resolution revealed the crucial difference between cells of the proximal tubules (PTs) and those of the distal tubules (DTs). Mitochondrial changes were consistent with the differing ATP dynamics in cells of the two regions, explaining the different sensitivity to ischemic reperfusion injury. A strong correlation emerged between ATP recovery of PT cells in acute phase and renal fibrosis in the chronic phase. Cold ischemia enhanced ATP recovery, providing a proof of concept for the possible protective value of renal hypothermia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      ATP distribution and dynamics has hindered further analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020050580","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T20:35:24Z","timestamp":1602534924000},"page":"2855-2869","source":"Crossref","is-referenced-by-count":53,"title":["Spatiotemporal ATP Dynamics during AKI Predict Renal Prognosis"],"prefix":"10.1681","volume":"31","author":[{"given":"Shinya","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamichi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"Advanced Scientific Research Leaders Development Unit, Gunma University Graduate School of Medicine, Maebashi, 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