Abstract: SA-PO1070
Chronic ASA Administration Exacerbates Renal Damage in Hypertensive Rats
Session Information
- Hypertension: Basic and Experimental - Treatment and Mechanisms
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Hypertension
- 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences
Authors
- Kennedy, Chris R., Kidney Research Centre, Ottawa, Ontario, Canada
- Thibodeau, Jean-Francois, Kidney Research Centre, Ottawa, Ontario, Canada
- Holterman, Chet E., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Carter, Anthony, Kidney Research Centre, Ottawa, Ontario, Canada
- Cron, Greg O, The Ottawa Hospital, Ottawa, Ontario, Canada
- Glikstein, Rafael, The ottawa Hospital, U of Ottawa, Ottawa, Ontario, Canada
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. (Aspirin (ASA), ibuprofen, naproxen) inhibit cyclooxygenases whose eicosanoid products buffer renal vasoconstriction in hypertension (HTN) but are contraindicated in hypertensive individuals as they increase risk for renal injury via decreased renal blood flow and GFR. However, there is little in vivo evidence of this phenomenon. We showed that in mice with HTN, vascular-specific deletion of the EP4 receptor (mimicking some of the downstream effects of NSAIDs) significantly reduced renal perfusion and exacerbated injury. The present study was undertaken to test the hypothesis that hypertensive renal injury would be more severe with chronic ASA administration.
Methods
Male Sprague-Dawley rats (n=5 per group) were implanted with Model 2002 Alzet osmotic minipumps loaded with vehicle or Angiotensin II (AngII) to deliver a dose of 400 ng/kg/min for 4 weeks. ASA was administered concurrently via drinking water (0.067 mg/ml) to yield a dose of 10mg/kg/day. Renal function was assessed by plasma creatinine using HPLC. Renal histology was assessed on Masson trichrome and PAS-stained kidney sections. At 0, 2, and 4 weeks, dynamic contrast-enhanced (DCE) MRI was performed using a 7T GE/Agilent MR901 and data analyzed with a two compartment filtration model (PMI, S. Sourbron) to estimate renal blood volume.
Results
After 4 weeks of AngII infusion, rats given daily ASA had significantly decreased bodyweight and appeared dehydrated. Surprisingly, despite comparable ASA dosing, this combination was associated with a 60% survival rate compared to 100% in all other groups. AngII/ASA decreased renal function vs all other groups as indicated by a doubling of plasma creatinine. Renal hypertrophy was similar in both AngII-treated groups. AngII treatment alone led to modest tubulointerstitial injury, characterized by increased tubulointerstitial fibrosis, tubular flattening/dilation and proteinaceous casts. However, the combination of ASA and AngII significantly increased the severity of tubular and glomerular injury, while DCE-MRI revealed profound loss of renal blood volume (P<0.006 vs all other groups).
Conclusion
The combination of AngII-mediated hypertension and chronic ASA intake accelerates renal function decline and injury.