In mammalian kidney, dopamine produced in the proximal tubule (PT) acts as an autocrine/paracrine natriuretic hormone that inhibits salt and fluid reabsorption in the PT. In high-salt-treated animals, PT dopamine activity increases and inhibits reabsorption, leading to increased salt and fluid delivery to the macula densa (MD) and subsequent natriuresis and diuresis. Regulated cyclooxygenase-2 (COX-2) in the MD represents another intrinsic system mediating renal salt and water homeostasis. Renal cortical COX-2 is inversely related to salt intake, and decreased extracellular NaCl stimulates COX-2 expression in cultured MD/cortical thick ascending limb cells. The current study investigated interactions between renal dopamine and cortical COX-2 systems. In rats fed a control diet, the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) or the DA1 receptor agonist SKF-81297 suppressed cortical COX-2 expression. High salt suppressed cortical COX-2 expression, which was attenuated by inhibition of dopamine production with benserazide or the DA1 receptor antagonist, SCH-23390. In contrast, l-DOPA or the dopamine-metabolizing enzyme inhibitor entacapone suppressed low-salt-induced cortical COX-2 expression. Inhibition of PT reabsorption with the carbonic anhydrase inhibitor acetazolamide suppressed cortical COX-2 expression. In contrast, treatment with distally acting diuretics led to elevation of cortical COX-2. These results indicate that dopamine modulates renal cortical COX-2 expression by modifying PT reabsorption.