Abstract: FR-PO388
Aristolochic Acid-Induced Aortic Stiffening in Mice Can Replicate Vascular Dysfunction Seen with CKD
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Brunt, Vienna E., University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
- Oh, Ester, University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
- Montford, John R., University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
- Jovanovich, Anna, University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
- Nowak, Kristen L., University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
- Furgeson, Seth B., University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
Background
Cardiovascular disease (CVD) is highly prevalent in CKD and the leading cause of death. Stiffening of large arteries precedes overt CVD and contributes to the pathogenesis. It is unclear if commonly used mouse models of CKD develop arterial stiffness.
Methods
Male and female C57Bl/6J mice (n=3-8/group) received 4 doses of aristolochic acid (AA) at 2 mg/kg and 8 mg/kg, respectively. Aortic pulse wave velocity (PWV), the gold-standard measure of arterial stiffness, was assessed in anesthetized mice 7-9 weeks after AA injections. Serum, aortas, and kidneys were collected at 9 (males) or 11 (females) weeks. To determine if increases in PWV were due to structural changes in the arteries, elastic modulus (EM) was determined in aorta rings by stress-strain testing. We compared CKD-induced fold increases in aortic PWV in mice and carotid-femoral PWV in patients with stage 3-4 CKD (17M/18F; age 66±7; eGFR 38±11 mL/min/1.73 m2)vs. age-matched controls (17M/18F; 63±7; eGFR 84±12 mL/min/1.73 m2).
Results
Male mice developed significant CKD as assessed by renal fibrosis (hydroxyproline content 6.3±1.4 mg/g vs. 3.2±0.8 mg/g protein, p<0.05) and renal dysfunction (blood urea nitrogen [BUN] 100±23 mg/dL vs. 33±9 mg/dL, p<0.05). Both aortic PWV (441±64 vs. 342±15 cm/s, p=0.05) and EM (6,525±392 vs. 5,011±898 kPa, p=0.07) were 1.3-fold higher with AA, and this increase in aortic stiffness was comparable to that observed in male CKD patients vs. controls (1.2-fold; 1,014±229 vs. 835±130 cm/s, p<0.01). Female mice also developed renal fibrosis (hydroxyproline 11.8±3.5 mg/g vs. 4.2±0.7 mg/g protein) and renal dysfunction (BUN 41±22 mg/dL vs. 21±4 mg/dL, p< 0.05). Despite less severe renal dysfunction than males, aortic PWV (408±43 vs. 356±16 cm/sec, p=0.08) and EM (7,905±1635 vs. 5,980±1190 kPa, p=0.09) were increased (1.2- and 1.3-fold higher) comparably to male mice and to female CKD patients (1.2-fold; 907±237 vs.789±141 cm/s, p=0.08). The range of aortic stiffening in female mice was wider than males, which was also reflected in our cohort of female patients.
Conclusion
AA administration produces CKD and aortic stiffening in both male and female mice that is similar to that seen in patients with CKD. This model may be a promising pre-clinical model to test vasculoprotective therapies in patients with CKD.