Insights into the biochemical mechanism of maleic acid-induced Fanconi syndrome

Abstract

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.

Carboplatin-induced Fanconi-like syndrome in rats: Amelioration by pentoxifylline

“…Decreased activity of the Na + /K + -ATPase leads to impaired membrane recycling activity and this was also observed in our model with carboplatin intoxication. As it is evident from Table 2, renal Na + /K + -ATPase activity was significantly reduced which stands in rank with other studies suggesting that renal insult lead to reduced Na + /K + -ATPase activity (Eiam-ong et al, 1995;Thevenod and Friedmann, 1999). We observed similar findings with the activity of other ATPases.…”

“…Specifically, this transport is effected by Na + -coupled mechanisms involving the Na + /K + -ATPase which maintains the low levels of intracellular low Na + levels essential for successful Na + -coupled (Eiam-ong et al, 1995). Decreased activity of the Na + /K + -ATPase leads to impaired membrane recycling activity and this was also observed in our model with carboplatin intoxication.…”

Induction of hepatocyte growth factor expression by maleic acid in human fibroblasts through MAPK activation

“…The biochemical mechanism responsible for maleic acid-induced alterations in renal tubular function is not completely understood, but it has been suggested that a decrease in Na þ , K þ -ATPase in proximal renal tubules underlies the many consequences of this model of Fanconi syndrome [Eiam-ong et al, 1995]. Under our experimental conditions, however, maleic acid did not show any effect on cellular viability.…”

Study of urinary 2-{[2-(acetylamino-2-carboxyethyl]sulfanyl}butanedioic acid, a mercapturic acid of rats treated with maleic acid

“…Maleic anhydride can be completely hydrolyzed to maleic acid (MA) at room temperature with a relative humidity of 96% (Rosenfel and Murphy, 1967). Harrison and Harrison (1954), Albander et al (1982), and Eiamong et al (1995) reported that MA could cause kidney effects to rats and dogs. The symptom is similar to the Fanconi syndrome in human, which the tubular reabsorption is malfunctioned, and glucose, amino acids, phosphate and bicarbonate could not be reabsorbed in proximal tubule (Albander et al, 1982;Harrison and Harrison, 1954).…”