Investigation of Tartaric Acid Enantiomer-Specific Nephrotoxicity and Citrate Synthase Inhibition in Madin-Darby Canine Kidney Cells In Vitro.

L-tartaric acid causes species-specific, transporter-mediated nephrotoxicity in dogs via mitochondrial citrate synthase inhibition.

This in vitro study investigated the enantiomer-specific nephrotoxicity of tartaric acid (TTA) using Madin-Darby Canine Kidney (MDCK) and human kidney (HK-2) cell lines over a 48-hour exposure period. The researchers examined how racemic and enantiomeric forms of TTA (5–50 mmol/L) affect cellular ATP levels and citrate synthase activity, while also exploring the role of organic anion transporters (OAT-1 and OAT-4) in TTA accumulation and toxicity. Key findings demonstrated that L-tartaric acid (L-TTA) caused significant ATP depletion (8.5–24.8%) and citrate synthase inhibition (36.5–45.0%) specifically in MDCK cells, with no comparable effect in HK-2 cells, indicating species-specific toxicity relevant to canine clinical cases. The mechanism appears to involve OAT-1-mediated intracellular accumulation of L-TTA combined with insufficient OAT-4-mediated efflux, leading to mitochondrial dysfunction via citrate synthase inhibition. Transporter transfection with OAT-4 reduced ATP loss by 8.0–11.2%, while probenecid (an OAT inhibitor) reduced cytotoxic effects by 11.7%. Co-treatment with oxaloacetate, a citrate synthase substrate, rescued ATP loss by 15.6%, suggesting a potential mitigation strategy. These findings provide mechanistic insight into why dogs are uniquely susceptible to TTA nephrotoxicity, as seen in grape and tamarind ingestion cases, and highlight transporter-based and substrate supplementation approaches as potential therapeutic targets to reduce acute kidney injury in canine patients.

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