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.

• Authors: Petra Szoleczky, Katalin Módis, Nóra Nagy, Zoltán Dóri Tóth, Douglas DeWitt, Csaba Szabó, Domokos Gero
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 517 Issue 1 Pg. 53-70 (Jan 01 2012) ISSN: 1096-0384 [Electronic] United States
• PMID: 22100704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Purine Nucleosides
• Adenosine Triphosphate
• Glucose
• Adenosine
• Oxygen

Topics

• Adenosine (pharmacology)
• Adenosine Triphosphate (metabolism)
• Animals
• Cell Hypoxia (drug effects)
• Cell Survival (drug effects)
• Cytoprotection (drug effects)
• Glucose (metabolism)
• Hypoxia (drug therapy, metabolism, pathology)
• Kidney (cytology, drug effects, metabolism, pathology)
• Kidney Tubular Necrosis, Acute (drug therapy, metabolism, pathology)
• LLC-PK1 Cells
• Oxygen (metabolism)
• Purine Nucleosides (pharmacology)
• Reperfusion Injury (drug therapy, metabolism, pathology)
• Swine