Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis

Abstract

Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS. Methods: Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs. Results: In ADR rats, expression of PAR2, PKCε and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1β, IL-6 and TNF-α. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-β1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-β1. Conclusions: Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-β1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients.

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

“…In a rat model of crescentic glomerulonephritis, administration of a PAR2 antagonist (GB88) reduced glomerular thrombosis and crescent formation; however, GB88 failed to protect against up‐regulation of Ccl2 or Tnf mRNA levels, interstitial macrophage infiltration or tubular damage – although little thrombosis was evident in the tubulointerstitial compartment . Administration of a different PAR2 antagonist (FSLLRY‐NH2) suppressed glomerular damage and renal impairment in rat model of adriamycin nephropathy, although tubulointerstitial damage was not assessed . On the other hand, Par2−/− mice show a modest, but significant, protection from adenine‐induced tubulointerstitial injury .…”

“…26 Administration of a different PAR2 antagonist (FSLLRY-NH2) suppressed glomerular damage and renal impairment in rat model of adriamycin nephropathy, although tubulointerstitial damage was not assessed. 27 On the other hand, Par2−/− mice show a modest, but significant, protection from adenine-induced tubulointerstitial injury. 28 Notably, this model features substantial interstitial fibrin deposition, indicating local thrombin generation, providing a mechanism for activation of tubular PAR2.…”

Aspergillus fumigatus Increased PAR-2 Expression and Elevated Proinflammatory Cytokines Expression Through the Pathway of PAR-2/ERK1/2 in Cornea

“…11 Moreover, PAR-2 plays a crucial role in different animal models of intestinal diseases, focal segmental glomerulosclerosis, skin inflammatory diseases, myocarditis, and airway inflammation. [12][13][14][15][16][17][18][19] Recent studies have shown that human corneal epithelial cells express PAR-2. In human corneal epithelial cells, inhibition of PAR-2 by a specific antagonist prevents proinflammatory cytokine production and reduces inflammation induced by Acanthamoeba plasminogen activator, a serine protease secreted by Acanthamoeba trophozoites, that is involved in the pathogenesis of Acanthamoeba keratitis, indicating that disruption of PAR-2 activity might have a major impact on preventing inflammatory responses in Acanthamoeba keratitis.…”

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

“…In focal segmental glomerulosclerosis, inhibition of PAR2 signaling by systemic administration of FSLLRY-NH 2 attenuated amplification of proinflammatory cytokines and exaggerated TGF-β1, thereby improving worsened renal functions and glomerular injury [ 55 ]. In the progressive renal disease IgA nephropathy, PAR2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells.…”