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Background and Purpose The function of the endocannabinoid system ( ECS) in renal tissue is not completely understood. Kidney function is closely related to ion reabsorption in the proximal tubule, the nephron segment responsible for the re-absorption of 70-80% of the filtrate. We studied the effect of compounds modulating the activity of cannabinoid ( CB) receptors on the active re-absorption of Na+ in LLC- PK1 cells. Experimental Approach Changes in Na+/ K+-ATPase activity were assessed after treatment with WIN55,212-2 ( WIN), a non-selective lipid agonist, and haemopressin ( HP), an inverse peptide agonist at CB1 receptors. Pharmacological tools were used to investigate the signalling pathways involved in the modulation of Na+ transport. Key Results In addition to CB1 and CB2 receptors and TRPV1 channels, the mRNAs encoding for enzymes of the ECS were also expressed in LLC- PK1. WIN (10−7 M) and HP (10−6 M) altered Na+ re-absorption in LLC- PK1 in a dual manner. They both acutely (after 1 min) increased Na+/ K+- ATPase activity in a TRPV1 antagonist-sensitive way. WIN's stimulating effect persisted for 30 min, and this effect was partially blocked by a CB1 antagonist or a PKC inhibitor. In contrast, HP inhibited Na+/ K+- ATPase after 30 min incubation, and this effect was attenuated by a CB1 antagonist or a PKA inhibitor. Conclusion and Implications The ECS is expressed in LLC- PK1 cells. Both CB1 receptors and TRPV1 channels regulate Na+/ K+- ATPase activity in these cells, and are modulated by lipid and peptide CB1 receptor ligands, which act via different signalling pathways. [ABSTRACT FROM AUTHOR]