Role of NaDC1 in Control of Urinary Excretion of α‐Ketoglutarate

Abstract

Recent studies have suggested that urinary α‐Ketoglutarate (α‐KG) increases with alkali loads and decreases with acid loads. Also luminal α‐KG stimulates distal bicarbonate secretion via the Oxgr1 (GPR99) receptor.To investigate the role of sodium dependent dicarboxylate transporter, NaDC1, in regulation of α‐KG excretion, we studied NaDC1 knockout (KO) and Heterozygous (Het) mice on normal diet and with 72 hrs acid loading. Plasma and urine samples were analyzed by LC/Mass Spec.Also 14C‐α‐KG uptake was studied using HRPE cells overexpressing hNaDC1 (CUBS) and the proximal tubule (PT) OK cell line. OK cells express a novel calcium (Ca)‐sensitive dicarboxylate transport system.In mice, fractional excretion (FE) of α‐KG was dramatically increased in the KO and Het mice (WT 0.38+/‐0.05, Het 2.8+/‐1.3, KO 4.7+/‐0.9; p<0.05). Acidosis lowered FE significantly in all mice.In CUBS α‐KG uptake decreased when competed with the dicarboxylate succinate (Suc 2 mM) in both normal and <60 µM Ca buffers (0.64±0.11 to 0.25±0.10 and 0.63±0.15 to 0.29±0.11, p<0.01).In OK cells, α‐KG uptake increased when extracellular Ca was lowered to <60 µM (1.7±0.49 vs 2.5±0.6, p<0.01). Transport decreased when competed with Suc in both Ca buffers (1.3±0.39 vs 1.6±0.34, p<0.01).NaDC1 transports α‐KG and is the predominant, but not exclusive, mechanism of control of distal α‐KG delivery. Also α‐KG is transported via a Ca‐sensitive transporter in OK cells. Furthermore based on the FEs > 1.0, α‐KG is secreted into the PT simultaneously with reabsorption.Thus NaDC1 in the PT regulates acid‐base transport in the distal tubule via the control of α‐KG transport. NaDC1 represents a novel mechanism of PT–distal tubule communication in the kidney.NIH/NIDDK