Abstract: FR-PO1227
Murine Model of Cardiovascular-Kidney-Metabolic Syndrome Demonstrates Compromised Function in the Ischemic Hind Limb
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Natrakul, Anna, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
- Lotfollahzadeh, Saran, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
- Paul, Herreet, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
- Bonifacio, Joshua, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
- Chitalia, Vipul C., Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
Background
Cardiovascular-Kidney-metabolic (CKM) syndrome is a public health problem in the US and results in premature CVD at a relatively preserved GFR. The molecular mediators of CKM are poorly understood, partly due to the lack of a reliable animal model. We set out to generate an animal model with renal and metabolic dysfunctions, using peripheral arterial disease (PAD) as a CKM manifestation.
Methods
C57BL/6 male and female mice were randomized into four groups: a normal diet (ND, controls), a 0.2% adenine diet (AD, a CKD model), a high-fat diet (HFD, a metabolic model), and a combination of HFD+AD (a potential CKM model). The mice underwent a hind limb ischemia, followed by an array of structural, endurance and post-exercise hyperemia assays.
Results
Compared to control mice, HFD+AD male mice had 23-50% higher weight and GFR than the AD group (P = 0.003). The kidneys of HFD+AD showed tubular atrophy, tubulointerstitial fibrosis, immune infiltration, glomerulomegaly, consistent with glomerular hyperperfusion, hypercholesterolemia, impaired glucose tolerance, adipophilin in the liver, an early marker of hepatic steatosis, and myocardial fibrosis.
The HFD+AD mice showed reductions in the hind limb perfusion ratios, microcapillary density, Type II muscle fibers, and increased muscle fibrosis, immune infiltration, and lowest cross-sectional muscle area. Female CKM mice revealed distinct differences from male mice. Compared to AD and HFD alone, female CKM mice exposed to HFD+AD demonstrated additive phenotypes in endurance assays (distance travelled, exhaustion time and grip strength) without a similar effect in post-ischemia perfusion, suggesting skeletal muscle and microcapillary dysfunction.
Conclusion
A combination of HFD+AD in mice displays features of CKD, metabolic disorders, and cardiovascular disease at a higher GFR, consistent with human CKM. This model can be explored to probe the mechanisms and heterogeneity and sex-specific differences in CKM.
Funding
- NIDDK Support