Protease-Activated Receptor 2 Blocking Peptide Counteracts Endotoxin-Induced Inflammation and Coagulation and Ameliorates Renal Fibrin Deposition in a Rat Model of Acute Renal Failure

Protease-Activated Receptor 2 Blocking Peptide Counteracts Endotoxin-Induced Inflammation and Coagulation and Ameliorates Renal Fibrin Deposition in a Rat Model of Acute Renal Failure. Shock, 2009. To the Editor: Jesmin et al. (1) showed that protease-activated receptor 2 (PAR-2) blocking peptide counteracts endotoxin-induced inflammation and coagulation and ameliorates renal fibrin deposition in a rat model of acute renal failure. In the first part of the article, it is shown that LPS administration to rats induced TNF-α expression, followed by a coagulant response leading to fibrin deposition in kidney tissues and subsequent elevations of creatinine and blood urea nitrogen. Interestingly, the pathological characteristics coincided with a time-dependent increase in PAR-2 expression in the glomeruli, the tunica intima of the small blood vessels, and in the interstitial areas. Based on these observations, the authors hypothesize that PAR-2 plays a causative role in mediating renal failure, and to prove or refute this hypothesis, a subgroup of rats was treated with a PAR-2 blocking peptide. Indeed, this peptide suppressed TNF-α expression, attenuated activation of the coagulation cascade, and decreased fibrin deposition in the glomeruli. Although the data very elegantly show that PAR-2 plays a key role in inflammation-coagulation-induced renal failure, the major importance of this article may be the use and availability of a PAR-2 antagonist. Protease-activated receptor 2 recently emerged as an essential player in pathophysiology, and PAR-2 inhibition seems an attractive therapeutic strategy for several inflammatory disorders (2-5). Large compound screens for PAR-2 antagonists by large pharmaceutical companies were, however, unsuccessful, and no proper PAR-2 antagonist has been available to the scientific community. We were thus pleasantly surprised by the article of Jesmin et al., although our enthusiasm faded a bit after carefully screening the "Materials and methods" section of the article. The authors use the sc-9278 P peptide of Santa Cruz Biotechnology, which, according to the Santa Cruz catalogue, is a blocking peptide available for competition studies with the sc-9278 antibody designed for the detection of Caenorhabditis elegans PAR-2. Indeed, sc-9278 P binds the PAR-2 antibody, thereby blocking the antibody from binding and detecting PAR-2 on either Western blots or tissue slides. Importantly, however, sc-9278 P is not known to inhibit PAR-2 cleavage, and the fact that this peptide sequence falls in the C-terminus of (C. elegans) PAR-2 suggests it does not indeed block PAR-2 cleavage. Thus, the observed beneficial effects of sc-9287 P in the rat model of acute renal failure are most likely not dependent on PAR-2 inhibition. In conclusion, sc-9287 P does not seem to be the eagerly awaited PAR-2 antagonist, and the aggravating role of PAR-2 in acute renal failure needs to be confirmed using alternative approaches, like, for instance, the use of PAR-2-deficient mice. C. Arnold Spek Lois W. Brüggemann Keren S. Borensztajn Center for Experimental and Molecular Medicine Academic Medical Center Amsterdam, the Netherlands