Abstract
Maleic acid (MA) has been shown to induce Fanconi syndrome via disturbance of renal energy homeostasis, though the underlying pathomechanism is still under debate. Our study aimed to examine the pathomechanism underlying maleic acid-induced nephrotoxicity. Methylmalonic acid (MMA) is structurally similar to MA and accumulates in patients affected with methymalonic aciduria, a defect in the degradation of branched-chain amino acids, odd-chain fatty acids and cholesterol, which is associated with the development of tubulointerstitial nephritis resulting in chronic renal failure. We therefore used MMA application as a control experiment in our study and stressed hPTECs with MA and MMA to further validate the specificity of our findings. MMA did not show any toxic effects on proximal tubule cells, whereas maleic acid induced concentration-dependent and time-dependent cell death shown by increased lactate dehydrogenase release as well as ethidium homodimer and calcein acetoxymethyl ester staining. The toxic effect of MA was blocked by administration of single amino acids, in particular L-alanine and L-glutamate. MA application further resulted in severe impairment of cellular energy homeostasis on the level of glycolysis, respiratory chain, and citric acid cycle resulting in ATP depletion. As underlying mechanism we could identify disturbance of calcium homeostasis. MA toxicity was critically dependent on calcium levels in culture medium and blocked by the extra- and intracellular calcium chelators EGTA and BAPTA-AM respectively. Moreover, MA-induced cell death was associated with activation of calcium-dependent calpain proteases. In summary, our study shows a comprehensive pathomechanistic concept for MA-induced dysfunction and damage of human proximal tubule cells.
Highlights
Renal proximal tubule epithelial cells play a central role in filtration, secretion, and resorption of diverse ions and metabolites [1]
Since succinic acid and fumaric acid are metabolized via the citric acid cycle and since their carbon backbones are used for intracellular production of amino acids and other compounds the use of these dicarboxylic acids as negative controls might be disadvantageous
For Human proximal tubule epithelial cells (hPTECs) are equipped with a functional methylmalonyl-CoA mutase, we first tested whether the applied Methylmalonic acid (MMA) was metabolized
Summary
Renal proximal tubule epithelial cells play a central role in filtration, secretion, and resorption of diverse ions and metabolites [1]. These processes require high amounts of molecular energy, provided by numerous mitochondria located on the basolateral side of the proximal tubule. Patients with inherited deficiency of energy metabolism often present with De Toni-Debré-Fanconi syndrome or–to a lesser degree–tubulointerstitial nephritis. Primary mitochondriopathies, such as respiratory chain defects, are often complicated by De Toni-Debré-Fanconi syndrome [2, 3] in which ATP depletion is likely to damage proximal tubule. It remains to be unravelled which additional factors precipitate-Fanconi syndrome or tubulointerstitial nephritis
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