The endocannabinoid system in renal cells: regulation of Na + transport by CB 1 receptors through distinct cell signalling pathways

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 ‐ PK 1 cells. Experimental Approach Changes in Na + / K + ‐ATPase activity were assessed after treatment with WIN 55,212‐2 ( WIN ), a non‐selective lipid agonist, and haemopressin ( HP ), an inverse peptide agonist at CB 1 receptors. Pharmacological tools were used to investigate the signalling pathways involved in the modulation of Na + transport. Key Results In addition to CB 1 and CB 2 receptors and TRPV 1 channels, the mRNAs encoding for enzymes of the ECS were also expressed in LLC ‐ PK 1. WIN (10 −7  M) and HP (10 −6  M) altered Na + re‐absorption in LLC ‐ PK 1 in a dual manner. They both acutely (after 1 min) increased Na + / K + ‐ ATP ase activity in a TRPV 1 antagonist‐sensitive way. WIN's stimulating effect persisted for 30 min, and this effect was partially blocked by a CB 1 antagonist or a PKC inhibitor. In contrast, HP inhibited Na + / K + ‐ ATP ase after 30 min incubation, and this effect was attenuated by a CB 1 antagonist or a PKA inhibitor. Conclusion and Implications The ECS is expressed in LLC ‐ PK 1 cells. Both CB 1 receptors and TRPV 1 channels regulate Na + / K + ‐ ATP ase activity in these cells, and are modulated by lipid and peptide CB 1 receptor ligands, which act via different signalling pathways.