Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia

Petra Szoleczky, Katalin Modis, Nóra Nagy, Zoltán Dóri Tóth, Douglas Dewitt, Csaba Szabo, Domokos Gero

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16 Citations (Scopus)

Abstract

Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.

Original languageEnglish (US)
Pages (from-to)53-70
Number of pages18
JournalArchives of Biochemistry and Biophysics
Volume517
Issue number1
DOIs
StatePublished - Jan 1 2012

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Renal Agents
LLC-PK1 Cells
Purine Nucleosides
Cell Hypoxia
Adenosine
Screening
Adenosine Triphosphate
Cell death
Metabolism
Glucose
Wounds and Injuries
Cell Death
Adenosine Kinase
Oxygen
Anaerobiosis
Purinergic Receptors
Inosine
Adenosine Deaminase
Poly(ADP-ribose) Polymerases
Caspases

Keywords

  • Acute renal failure
  • Acute tubular necrosis
  • Adenosine
  • Cell-based screening
  • Inosine
  • Ischemic kidney injury

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: Purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia",
abstract = "Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.",
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AU - Szoleczky, Petra

AU - Modis, Katalin

AU - Nagy, Nóra

AU - Dóri Tóth, Zoltán

AU - Dewitt, Douglas

AU - Szabo, Csaba

AU - Gero, Domokos

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AB - Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.

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