PAR-2 DOES NOT CONTRIBUTE TO TUBULAR DAMAGE OR RENAL FIBROSIS IN THE OBSTRUCTED KIDNEY.

Y HAN1,2,  F MA1,2, E OZOLS1,2,  P CHEW1,2, D VESEY3, G GOBE3,  C MORAIS4, R LOHMAN4, J SUEN4,  D FAIRLIE4, D NIKOLIC-PATERSON1,2
1Dept of Nephrology, Monash Medical Centre, Clayton, Australia, 2Centre for Inflammatory Diseases, Monash University, Clayton, Australia, 3Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Australia, 4Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia

Aim: To determine whether Protease Activated-Receptor-2 (PAR-2) contributes to tubular cell activation and renal fibrosis in the obstructed kidney.
Background: Activation of PAR2 has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR-2 in cultured tubular epithelial cells induces cell proliferation and secretion of fibronectin, CCL2 and TGF-β1; suggesting that PAR-2 signalling may promote tubulointerstitial inflammation and fibrosis. We tested this hypothesis in the unilateral ureteric obstruction (UUO) model in which activation of tubular epithelial cells drives tubulointerstitial inflammation and fibrosis.
Methods: UUO surgery was performed in groups (n=10) of Par2-/- and WT (littermate control) C57BL6/J mice which were killed 7 days later.
Results: WT mice exhibited a 5-fold increase in PAR-2 mRNA levels in the UUO kidney. In situ hybridisation localised PAR-2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in PAR-2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Renal fibrosis was not different between Par2-/- and WT UUO in terms of collagen IV deposition and accumulation of α-SMA+ myofibroblasts, while increased mRNA levels for col I, col IV, α-SMA, CTGF and TGF-β1 were also not different. Similarly, no difference in up-regulation of macrophage markers (CD68 and CD206) or inflammation markers (TNF-α, NOS-2, MCP-1, IL-36α) was evident. Tubular damage was equivalent between Par2-/- and WT mice based on the percentage of damaged tubules on PAS stained sections, increased levels of KIM-1 mRNA and decreased levels of α-Klotho mRNA.
Conclusions: PAR-2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of renal inflammation or fibrosis.


Biography:
Dr Nikolic-Paterson is form the Department of nephrology at Monash Medical Centre and his research interests focus on the mechanism of renal inflammation and fibrosis.

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