Exogenous adenosine triphosphate (ATP) preserves proximal tubule microfilament structure and function in vivo in a maleic acid model of ATP depletion.
The hallmark of ischemic acute renal failure is a rapid and early decline in proximal tubule ATP. Since we have previously shown that over half of apical microfilament losses occur within the first 5 min of experimental ischemic injury, we postulated that microfilament (F-actin) structure and cellular location are dependent on cellular ATP levels. To test this hypothesis, we used maleic acid to selectively inhibit renal cortical ATP production in vivo. Maleic acid significantly decreased tissue ATP and apical F-actin in a dose-dependent manner relative to equimolar sodium chloride controls, yet higher doses of maleic acid quantitatively resulted in net actin polymerization, primarily in the cytoplasm. Functionally, maleic acid decreased glomerular filtration rate (GFR) and tubular reabsorption of sodium (TRNa) in a dose-dependent manner relative to sodium chloride controls. Administration of exogenous ATP resulted in significant increases in tissue ATP, net actin depolymerization, and relocation of F-actin from the cytoplasm back to the apical surface coinciding with increases in GFR and TRNa. Thus, ATP depletion induced by maleic acid resulted in significant cytoskeletal and functional alterations that were ameliorated by exogenous ATP. We therefore conclude that the structure and cellular location of F-actin necessary for normal functioning of proximal tubule cells in vivo is dependent on tissue ATP levels.
Kellerman
P S
PS
Department of Internal Medicine, University of California, Davis, Sacramento 95817.
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D000199:Actins / Q000032:analysis; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007672:Kidney Cortex / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence
D000199:Actins; D008298:Maleates; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C030272:maleic acid