The endocannabinoid system in renal cells: regulation of Na+ transport by CB1 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- 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]