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.