Protection of the kidney against ischemic injury by inhibition of 5'-nucleotidase.
We have evaluated the impact of inhibiting adenine nucleotide dephosphorylation on the metabolic and functional consequences of renal ischemia. Intramuscular injection of the ADP-analogue adenosine alpha, beta-methylene diphosphate (AMP-CP) achieved a 70% reduction in 5'-nucleotidase activity, as measured in crude extracts of rat kidney. AMPCP-treated animals had an increased residual nucleotide pool at the end of 45 min of ischemia compared with untreated rats. Assessment of renal ATP by 31P-nuclear magnetic resonance (31P-NMR) in vivo during reflow demonstrates the following: 1) higher rapid initial recovery of ATP (69.3 +/- 1.2 vs. 50.0 +/- 0.5% control value, P less than 0.005), 2) accelerated rate of ATP restoration (0.20 +/- 0.02 vs. 0.11 +/- 0.01% control/min, P less than 0.005), and 3) significantly enhanced renal ATP content after 120 min (93.6 +/- 2.0 vs. 63.1 +/- 0.7% control, P less than 0.005). Kidney function, as measured by the rate of inulin clearance 24 h after the insult, was also significantly improved in AMPCP-treated rats (725 +/- 50 vs. 313 +/- 28 microliters.min-1.100 g body wt-1). Thus inhibition of 5'-nucleotidase results in enhanced metabolic and functional recovery from a renal ischemic insult.
Van Waarde
A
A
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06510.
Stromski
M E
ME
Thulin
G
G
Gaudio
K M
KM
Kashgarian
M
M
Shulman
R G
RG
Siegel
N J
NJ
D015720:5'-Nucleotidase; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D007511:Ischemia / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply*; D007700:Kinetics; D008297:Male; D009708:Nucleotidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects*
D007042:Hypoxanthines; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D019271:Hypoxanthine; D000244:Adenosine Diphosphate; D009708:Nucleotidases; D015720:5'-Nucleotidase