Physiological and pathophysiological role of PARs in kidney(s)
Several studies have reported the physiological and pathophysiological role of PARs in the kidneys and the main study highlights include:
1) In the renal cortical collecting duct cells, PAR2 activation increases the intracellular calcium ion and regulates the calcium-dependent chloride secretion [2, 40].
2) Activation of PAR2 also regulates fluid reabsorption by facilitating sodium reabsorption in the cortical collecting duct cells, whereas it also prevents potassium secretion via activating the ERK pathway [29, 30, 41]. This was evident from the experimental study, which showed that administration of trypsin, which is a known activator of PAR2 induced sodium reabsorption in the cortical collecting duct cells of WT mice but was not observed in PAR2-/- mice. Furthermore, based on the fact that the expression of ERK is up-regulated by the PAR2 activation, the mechanism involved was investigated, which revealed that phosphorylation of ERK is increased upon the activation of PAR2. Moreover, inhibition of ERK by U0126 significantly reduced the trypsin-dependent PAR2 induced sodium reabsorption. Additionally, potassium homeostasis was found to be regulated by PAR2 and potassium secretion was inhibited in cortical collecting duct cells of mice with trypsin-induced PAR2 activation [41].
3) PAR2 is also involved in the regulation of inflammation, cell growth and repair [30]. This was noticeable from the previous investigations [42-44], which showed that in primary cultures of human proximal tubule cells (PTC), activation of PAR2 by its activating peptide SLIGKV-NH2 resulted in increased monocyte chemoattractant protein-1(MCP-1) levels, which is a pro-inflammatory molecule, and in together with its chemotactic actions, it also promotes inflammatory responses with the production of IL-6, IL-8 in the tubular cells. Additionally, activation of PAR2 also promotes the proliferation of epithelial and endothelial cells, thereby suggesting the role of PAR2 in cell growth and repair. [42-44].
4) The subtypes PAR1 and PAR2 are demonstrated to be involved in the regulation of renal hemodynamics. Notably, an in-vitro study using an isolated rat kidney perfusion model showed the opposite effects of PAR1 and PAR2 in the regulation of renal hemodynamics. The activation of PAR1 by agonist TFLLR or thrombin produced renal vasoconstriction and decreased both renal perfusion flow rate (RPF) and glomerular filtration rate (GFR), which was completely diminished by inhibition of protein kinase C. On the other hand, PAR2 activation by agonist, SLIGRL-NH2 or trypsin does not show any effect on the basal RPF (renal plasma flow) and GFR, but with the administration of angiotensin II (ANG II) prior to agonist treatment, abolished Ang-II induced vasoconstriction and resulted in renal vasodilation and improved GFR [2, 29]. This indicates that PAR2 activation regulates renal perfusion by counteracting the Ang II effects on renal hemodynamics. During pathological conditions many proteases gets activated, which induce up-regulation in the expression of PARs, indicating that these receptors have a prominent pathological roles in the progression of kidney disease [29, 36]. Various experimental studies on PARs in kidney diseases have been summarized in table 2, and also flow diagram summarizing the pathophysiological role PAR receptors in kidney disease progression is shown in figure 1 [37, 45].