Role for cannabinoid receptors in human proximal tubular hypertrophy

Endogenous endocannabinoids bind to cannabinoid receptors; namely CB1, CB2, TRPV1 and GPR55, to activate intracellular pathways that control many cellular functions. Elevated levels of endocannabinoids have been identified in diseases such as obesity and diabetes, with the onset of diabetic nephropathy associated with proximal tubule hypertrophy. Recent research has identified a role for CB1 in apoptosis in human proximal tubular (HK2) cells, however the role of the other receptors has not been investigated. We investigated if the cannabinoid receptors played a role in hypertrophy in HK2 cells. Characterisation of HK2 cells demonstrated that mRNA and protein for CB1, CB2, TRPV1 and GPR55 occurs in these cells. Importantly, activation of the cannabinoid receptors with anandamide significantly increases hypertrophy in HK2 cells. In general, treatment with CB1 antagonist AM-251, reduces hypertrophy while treatment with CB2 (AM-630) and TRPV1 (SB-366791) antagonists increases hypertrophy. Targeting a cannabinoid receptor sensitive to O-1918 in HK2 cells did not alter proximal tubule cell hypertrophy. Therefore it is likely that in human proximal tubule, these receptors regulate cellular function by activating different cell signalling pathways. Nonetheless, we have identified a role for cannabinoid receptors in proximal tubule cells which may provide novel therapeutic targets for the treatment of diabetes and obesity.