PURPOSE: The present study was aimed to determine whether there exist an altered regulation of tubular transporters and nitric oxide system in the kidneys in maleic acid-nduced metabolic acidosis. METHODS: Male Sprague-awley rats were treated with maleic acid (2 mmol/kg, every 24 hours, intraperitoneally) for 2 days. Control rats were injected with saline. At 24 hours following the second injection, rats were killed by decapitation. Plasma HCO3-and anion gap were measured. The protein expression of type 3 Na+/H+ exchanger (NHE3), type 1 Na+:HCO3- cotransporter (NBC1), and aquaporin (AQP)-1 in the cortex of the kidneys was determined by Western blot analysis. In addition, the expression of isoforms of nitric oxide synthase (NOS) was determined. Contents of nitric oxide metabolites (nitrite/ nitrate, NOx) were also measured in urine by colorimetric assay. RESULTS: Plasma concentrations of HCO3- were significantly decreased following the treatment of maleic acid, while plasma anion gap was did not differ between the experimental and the control groups. In the experimental group, the protein expression of NHE3 was significantly increased in the cortex of the kidney although the expression of NBC1 was not altered significantly. The expression of inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) was significantly increased in the cortex of the kidney. Accordingly, urine NOx contents were increased in the experimental group. In contrast, the expression of AQP1 was not altered. CONCLUSION: These results indicated that upregulation of NHE3 and nitric oxide system may play a role in regulation of acid-ase balance.