Potential physiological and pathophysiological roles for protease-activated receptor-2 in the kidney

The protease-activated receptor-2 (PAR-2), the second of four members of a unique subfamily of G-protein coupled receptors, is abundantly expressed in the kidney. In a similar manner to other PAR cleavage of its extracellular N-terminus exposes a tethered ligand, SLIGKV in humans, which acts as an intramolecular ligand to activate itself. In the kidney, PAR-2 expression has been variably reported in collecting duct cells, mesangial cells, interstitial fibroblasts, vascular endothelial cells, vascular smooth muscle cells and proximal tubular cells. Despite this renal expression data, the function of PAR-2 in the kidney remains unknown. More than 15 different mammalian serine proteases have been shown to activate PAR-2 in an in vitro setting, but it is still unclear which of these are physiologically relevant activators of PAR-2 in specific tissues. Their identification could provide novel therapeutic targets. PAR-2 activates a number of down-stream signalling molecules that include protein kinase C, extracellular signal regulated kinase and nuclear factor kappa-B. Proteases that can activate PAR-2 are generated and released from cells during injury, inflammation and malignancy and can thus signal to cells under these conditions. Potential physiological and pathophysiological roles for PAR-2 in the kidney include the regulation of inflammation, blood flow, and ion transport and tissue protection, repair and fibrosis. In this review the potential roles of PAR-2 in the kidney are highlighted and discussed.