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Abstract: FR-PO121

PGE2 EP1 Receptor Deletion Worsens Hypertensive Kidney Disease in TTRhRen Mice, Promoting Glomerular Podocyte and Endothelial Cell Injury

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Nasrallah, Rania, Kidney Research Centre, Ottawa, Ontario, Canada
  • Robertson, Susan June, The Ottawa Hospital, Ottawa, Ontario, Canada
  • Ghossein, Jamie, University of Ottawa, Ottawa, Ontario, Canada
  • Xiao, Fengxia, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Burger, Dylan, Kidney Research Centre, Ottawa, Ontario, Canada
  • Hébert, Richard L., Kidney Research Centre, Ottawa, Ontario, Canada
Background

Prostaglandin E2 (PGE2) regulates glomerular hemodynamics, renin secretion, and tubular transport. PGE2 EP1 receptors promote renal injury in diabetes, and EP1 deletion improves hyperfiltration, albuminuria, and fibrosis in several diabetic models. The role of PGE2/EP1 in hypertension remains controversial. The purpose of this study was to examine the contribution of PGE2/EP1 to long-standing hypertensive kidney disease.

Methods

Male FVB EP1-/- mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 wks of age in 4 groups: wild-type (WT), EP1-/-, Htn, HtnEP1-/-. Blood pressure was measured by tail vein, and glomerular filtration rate (GFR) was estimated by FITC-inulin clearance. Urine was collected over 24 hrs in metabolic cages, and urine albumin was measured by ELISA. Total RNA was isolated from renal cortex for quantitative PCR analysis. Ultrastructural injury was assessed by electron microscopy. Urine microparticles were characterized by flow cytometry.

Results

Systolic blood pressure was elevated in Htn mice (150 mmHg) compared to WT mice (110 mmHg), but unchanged by EP1 deletion. However, EP1 deletion resulted in significantly increased albuminuria (>10-fold WT and >3-fold Htn) and reduced FITC-inulin clearance (50% of WT) in HtnEP1-/- mice, independent of blood pressure changes. Cyclooxygenase (COX)-2 mRNA was increased in all mice lacking EP1. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP1-/- mice compared to Htn and WT mice: including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from the glomerular basement membrane with focal subendothelial cell debris. This injury was associated with increased podoplanin-positive urine microparticles indicative of podocyte damage.

Conclusion

EP1 deletion increases albuminuria and reduces GFR in Htn mice, due to significant injury to podocytes and glomerular endothelium. Taken together, the data suggests that EP1 receptors play a protective role in hypertensive kidney disease. Highlighting the importance of carefully examining disease context (eg. diabetes vs hypertension) when characterizing underlying disease processes.

Funding

  • Government Support - Non-U.S.