9. Possible role of PAR2 blockade in sepsis associated kidney
injury
Sepsis is a life-threatening condition that might involve the amplified
immune response of the body towards the invaded pathogen resulting in
multiple organ failures including AKI [102]. In general, it appears
that the early phase of sepsis follows dramatic hyper-responsiveness
towards pro-and anti-inflammatory cytokines that are liberated in the
blood circulation, and exposure of local adhesion receptors to surface
of activated endothelial cells resulting in platelet aggregation,
microthrombi formation accompanied with enhanced recruitment of immune
cells [103,104]. However, the later stage of sepsis is characterized
by immunosuppression of the immune system [105]. Lipopolysaccharide
(LPS), mainly produced by gram-negative bacteria, is one of the widely
used toxins to provoke an immune response that initiates kidney injury
[106]. Endothelin-1 (ET-1) is an important vasoconstrictor peptide
that is produced abundantly by the segments of the nephron mainly by
mesangial cells, juxtaglomerular cells, renal endothelial, and principle
cells of collecting duct and also by tubular region [107].
Up-regulation of renal endothelin-1 level leads to renal injury mainly
by damaging podocytes, also promoting ER-stress and apoptosis induced
tubular injury [108]. Specifically, the role of ET-1 has been shown
to be pivotal in the inflammatory response involved in
endotoxemia-related AKI. Notably, a study has investigated the effects
of PAR2 blockade in lipopolysaccharide (LPS) induced elevation in the
endothelin-1 peptide. (Figure-03) [109-111]. In the endotoxemic rat
model [109], LPS was intraperitoneally administered as a single dose
of 15 mg/kg. This toxin challenge resulted in altered hemodynamic and
impaired renal functions as depicted by reduced mean blood pressure and
gradual increase in creatinine and BUN in the serum when observed at
1hr, 3hr, 6hr, and 10th hr. Furthermore, both serum
and tissue levels of iNOS, TNF-α, and ET-1 expressions were found to be
elevated during the initial 1 and 3 hours followed by a significant
decline in these levels in later hours of study after LPS
administration. Moreover, the histopathological analysis showed focal
tubular dilation accompanied by mild swelling and change in thickness of
epithelial cells after LPS administration, which are indications of a
septic kidney injury. Notably, administration of PAR2 blocker peptide
(sc-9278 P) 30 minutes prior to LPS infusion could not normalize the
renal dysfunction in LPS induced endotoxemic rats as depicted by
unchanged levels of elevated serum creatinine and BUN levels after 3 hr.
However, PAR2 blockade has effectively reduced the elevated renal tissue
level of ET-1 and TNF-α levels, and also iNOS protein expression after 3
hours of sc-9278 P in LPS subjected rats [109]. This clearly
suggested that PAR2 contributes to LPS induced renal dysfunction partly
by the production of vasoconstrictive peptide ET-1, iNOS, and
inflammatory cytokines release by possibly activating the NO pathway.
However, PAR2 inhibition is not sufficient to attenuate functional
alterations in septic rats perhaps due to a lack of binding specificity
for renal tubular regions.