Renalase is a kidney secreted catecholamines-degrading enzyme whose expression and activity are down-regulated by increased dietary phosphate. A renalase knockout (KO) mouse model was used to explore the mechanisms mediating renalase's effect on phosphate excretion. Compared to wild type (WT) mice maintained on a regular diet, KO mice show decreased serum PO₄- (KO=5.3±0.2 vs WT=6.0±0.1, n= 6, p<0.04), and increased urinary PO₄- excretion (urine PO₄-/creatinine: KO=7.7±0.3 vs WT=6.1±0.3, n=6, p<0.02). However, both WT and KO mice respond similarly to PO₄- restriction by increasing renal COMT-1 activity and markedly decreasing PO₄- excretion, which excludes an intrinsic renal defect in the KO. Renal sodium-phosphate co-transporter, Npt2a, and sodium proton exchanger, NHE3 expression, and MAO-A and B activity did not differ between WT and KO. Only catechol-O-methyl transferase (COMT) expression and activity were significantly increased in KO mice. In spite of that, urinary dopamine increased by 2 fold, while urinary L-DOPA excretion decreased by 2 fold, indicating an up-regulation of renal DA synthesis. These data indicate that renalase deficiency is associated with increased renal DA synthesis, stimulated PO₄- excretion, and moderately severe hypophosphatemia. The signal to increase renal DA synthesis is strong as it overcomes a compensatory increase in COMT activity.