Hypoxia-induced amphiphiles inhibit renal Na+, K(+)-ATPase.
We have characterized the effects of hypoxia on carnitine metabolism in proximal tubules. Hypoxia for 10 minutes resulted in a significant increase in the mass of long chain acylcarnitines (LCAC) (control 53 +/- 20 vs. hypoxia 118 +/- 38 pmol. mg-1 protein). Since LCAC are proximal metabolites in the beta-oxidation of fatty acids, these data suggest that inhibition of fatty acid oxidation occurs during hypoxia in the proximal tubule. In addition to LCAC accumulation, hypoxia resulted in a significant increase in the mass of lysoplasmenylcholine LPLasCho (control 62 +/- 15 pmol/mg vs. 20 min hypoxia 146 +/- 21 pmol/mg protein, N = 4) and also in increases in the mass of monoacyl LPC (control 122 +/- 24 pmol/mg protein vs. 283 +/- 35 pmol/mg protein after 40 min of hypoxia). We tested the possibility that these compounds that accumulate during hypoxia could inhibit proximal tubule Na+, K(+)-ATPase. LPC, LPlasC, and LCAC inhibited proximal tubule nystatin-stimulated oxygen consumption (QO2) and proximal tubule Na+, K(+)-ATPase activity in a dose-dependent manner. In addition, LPC, LPlasC, and LCAC directly inhibited' (65%, 80%, and 60%, respectively) Na+, K(+)-ATPase activity purified from kidney cortex at similar concentrations at which they accumulate during hypoxia (above 25 microM). The present data suggest that amphiphile accumulation may have a potential pathophysiologic role in the proximal tubule during renal ischemia.
Schonefeld
M
M
Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
Noble
S
S
Bertorello
A M
AM
Mandel
L J
LJ
Creer
M H
MH
Portilla
D
D
D000818:Animals; D002331:Carnitine / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D005227:Fatty Acids / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D012754:Sharks; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D005227:Fatty Acids; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; C021215:lysoplasmalogens; D000254:Sodium-Potassium-Exchanging ATPase; D002331:Carnitine