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Abstract: PO0434

Role of Protease-Activated Receptor 1 (PAR1) in Glomerular Filtration Barrier Integrity

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Brodsky, Sergey V., The Ohio State University, Columbus, Ohio, United States
  • Medipally, Ajay kumar, The Ohio State University, Columbus, Ohio, United States
  • Xiao, Min, The Ohio State University, Columbus, Ohio, United States
  • Doraiswamy, Mohankumar, The Ohio State University, Columbus, Ohio, United States
  • Kerlin, Bryce A., Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Protease-activated receptors (PARs) play a significant role in the regulation of angiogenesis and fibrosis. Their role in the regulation of glomerular filtration barrier (GFB) function is incompletely elucidated. We had demonstrated that PAR1 inhibition with SCH79797 results in glomerular hemorrhage and acute kidney injury in the 5/6 nephrectomy rats (5/6NE), effects similar to those of a direct thrombin inhibitor (dabigatran) and mimic features of anticoagulant-related nephropathy in humans.
The aim of the current study was to investigate potential synergistic effects of dabigatran with PAR1 inhibition or agonism in 5/6NE.

Methods

Three weeks after surgery 5/6NE rats were treated with dabigatran (150 mg/kg/day) alone or with PAR-1 inhibitor SCH79797 (1.0 mg/kg/day and 3.0 mg/kg/day) or PAR1 activation peptide, TFLLR-NH2 (0.25 mcmol/kg/day and 0.5 mcmol/kg/day). Serum creatinine (SCr), activated partial thromboplastin time (aPTT), and hematuria were measured daily; kidney morphology was evaluated at the end of the study.

Results

As expected, treatment with PAR1 modulators did not alter the anticoagulant effects of dabigatran and did not prolong aPTT when used alone. Both SCH79797 and TFLLR-NH2 aggravated increased SCr levels induced by dabigatran in a dose-depended manner in the 5/6NE. Interestingly, both PAR1 activation peptide and PAR1 inhibition increased SCr in 5/6NE when used alone (Fig 1). Neither SCH79797 nor TFLLR-NH2 significantly affected dabigatran-induced hematuria in 5/6NE. Morphologically, 5/6NE treated with dabigatran, SCH79797 and TFLLR-NH2 alone or in combination, had red blood cell casts in the tubules and acute tubular epithelial cell injury.

Conclusion

PAR1 homeostasis is necessary to maintain GFB integrity in 5/6NE. Pharmacological activation or inhibition of PAR1 results in glomerular hematuria and acute kidney injury in 5/6NE. These effects are similar to those of dabigatran-mediated thrombin inhibition in 5/6NE, suggesting that the thrombin-PAR1 signaling axis is important to GFB function.

*- p<0.05 compared to 5/6NE control
# - p<0.05 compared to 5/6NE + dabigatran

Funding

  • NIDDK Support