Insights into the biochemical mechanism of maleic acid-induced Fanconi syndrome.
Maleic acid administration is known to produce the Fanconi syndrome, although the biochemical mechanism is incompletely understood. In this study the effect of a single injection of maleic acid (50 mg/kg body wt, i.v.) on the rat renal ATPases was examined. Maleic acid rapidly caused bicarbonaturia, natriuresis, and kaliuresis. When nephron segments were microdissected, there was an 81 +/- 2% reduction in proximal convoluted tubule (PCT) Na-K-ATPase activity (P < 0.005) and a 48 +/- 4% reduction in PCT H-ATPase activity (P < 0.01). Enzyme activity (Na-K-ATPase, H-ATPase, H-K-ATPase) in the medullary thick ascending limb of Henle's loop and distal nephron segments was normal. In vitro, maleic acid (1 and 10 mM) inhibited Na-K-ATPase in PCT, but it had no effect on H-ATPase in PCT. Prior phosphate infusion to maleic acid-treated rats attenuated urinary bicarbonate wastage by 50% (P < 0.05); activity of proximal tubule Na-K-ATPase and H-ATPase activities were partially protected as compared to the animals given maleic acid alone (P < 0.05). Renal cortical ATP levels were not altered at the concentration of maleic acid used in this study (that is, 50 mg/kg body wt), but higher doses of maleic acid (that is, 500 and 1000 mg/kg body wt) caused ATP levels to fall. Maleic acid did not affect cortical medullary total phosphate concentration, however, P32 turnover (1 and 24 hr) was altered by prior phosphate infusion. A protective effect of prior phosphate loading on the membrane bound Pi pool (insoluble) was seen while the cytosolic Pi pool (soluble) was not different from control. Thus, maleic acid-induced "Fanconi" syndrome likely results from both direct inhibition of proximal tubule Na-K-ATPase activity and membrane-bound phosphorus depletion. The former mechanism would reduce activity of the sodium-dependent transporters (that is, Na/H antiporter), while the latter would inhibit the electrogenic proton pump (H-ATPase). The combination of reduced proximal tubule Na-H exchange and H-ATPase activities would markedly inhibit bicarbonate reabsorption and result in the metabolic acidosis universally seen in the Fanconi syndrome.
Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, USA.
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Eiam-ong
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Spohn
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Kurtzman
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Sabatini
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005198:Fanconi Syndrome / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology; D010758:Phosphorus / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014018:Tissue Distribution
D008298:Maleates; D010710:Phosphates; D010758:Phosphorus; D000255:Adenosine Triphosphate; C030272:maleic acid; D017506:H(+)-K(+)-Exchanging ATPase; D000254:Sodium-Potassium-Exchanging ATPase