Dietary NaCl modulates the urinary organic metabolite profile: influence of the organic anion transporter OAT3 (892.34)

Abstract

The organic anion transporter 3 (OAT3) mediates uptake of organic anions across the basolateral membrane of the proximal tubule in exchange for α‐ketoglutarate. Mice lacking OAT3 have reduced blood pressure, but the underlying mechanism is unclear. Renal metabolism is closely linked to transport function, but little is known about the metabolic response of the kidney to changes in NaCl diet. Here we show that a low NaCl diet (0.01%) increases renal OAT3 protein expression by 50‐60% vs. high NaCl diet (4%) and that NaCl intake has distinct effects on the urinary metabolite pattern in wild‐type mice (WT): α‐ketoisocaproate, α‐ketoisovalerate, α‐keto‐3methyl valerate, and α‐ketoglutarate were not detectable in urine under high NaCl diet, whereas a low NaCl diet was associated with mean urinary concentrations of 50‐300 ng/µmol creatinine (each P<10‐6). Low NaCl diet was also associated with 10‐20 fold higher urinary excretion of pyruvate (P<10‐3). In contrast, urinary excretion of benzoate, 3‐OH‐butyrate, malonate, and succinate were lower under low vs. high NaCl diet (each P<10‐3), the latter being also an activator of GPR91, which stimulates renin release. Similar differences were observed in Oat3‐/‐ mice, except that a consistent and significant stimulatory effect of low NaCl diet on urinary α‐ketoglutarate was not detected. We conclude that dietary NaCl intake has a distinct influence on the urinary organic metabolite pattern, including substrates and components of the citric acid cycle and other molecules used as energy source. This pattern is mainly independent of OAT3, even though dietary NaCl regulates renal expression of OAT3. Grant Funding Source: Supported by NIH grants R01HL94728, R01DK56248, P30DK079337, and the Department of Veterans Affairs