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].