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Abstract: FR-PO333

Protease-Activated Receptor-1 Deficiency Protects Against Glomerular and Endothelial Injury in Type 2 Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Lok, Sarah W.Y., The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Yiu, Wai Han, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Zou, Yixin, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Ma, Jingyuan, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Feng, Yuchen, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Lai, Kar Neng, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Tang, Sydney C.W., The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
Background

We recently showed that depletion of protease-activated receptor-1 (PAR-1) confers kidney protection in rodent models of CKD. Whether the same phenomenon may be observed in the diabetic kidney remains unknown.

Methods

We generated a novel double transgenic PAR-1 KO db/db mouse and observed its pathophysiology weeks in comparison to the respective wild-type and non-diabetic control animals. Fasting, non-fasting serum and urine were collected for up to week 24 of age. Vascular permeability assay of Evan’s blue extravasation was performed to assess endothelial injury in the kidneys. Kidney function and histological damage were determined post-mortem. Six animals were included in each experimental group for analysis.

Results

PAR-1 deficiency significantly reduced fasting blood glucose level and glucose tolerance by OGTT associated with higher serum insulin levels in db/db mice. Morphologically, db/db control mice developed glomerular hypertrophy and tubulointerstitial damage compared to db/+ non-diabetic mice, whereas db/db;Par1-/- mice displayed less mesangial expansion and tubular dilation. db/db;Par1-/- mice had lower albuminuria with restoration of nephrin and WT-1 levels in the glomerulus compared to db/db controls. PAR-1 deficiency also preserved endothelial integrity and capillary permeability, along with an increase of VEGFA levels in db/db kidneys.

Conclusion

PAR-1 depletion confers kidney protection by reducing vascular damage and glomerular injury in experimental type 2 diabetic nephropathy. These novel findings suggest the potential of a PAR-1 targeted therapeutic strategy in diabetic nephropathy. Funding: Research Grants Council of Hong Kong (General Research Fund,
grant no. 17118720)

Funding

  • Government Support – Non-U.S.