A Murine Model of Cardiovascular-Kidney-Metabolic Syndrome Demonstrates Compromised Limb Function in the Ischemic...

Area of Science:

• Cardiovascular research
• Nephrology
• Metabolic disease research

Background:

• Cardiovascular-Kidney-Metabolic (CKM) syndrome is a significant public health concern in the US, leading to premature cardiovascular disease (CVD) with relatively preserved glomerular filtration rate (GFR).
• Understanding the molecular mechanisms of CKM is hindered by the absence of a suitable animal model.
• This study aimed to develop an animal model exhibiting renal and metabolic dysfunctions, incorporating peripheral arterial disease (PAD) as a CKM manifestation.

Purpose of the Study:

• To generate a novel mouse model that recapitulates key features of CKM.
• To utilize peripheral arterial disease (PAD) as a manifestation of CKM within this model.
• To investigate the underlying mechanisms and sex-specific differences in CKM.

Main Methods:

• Male and female C57BL/6 mice were assigned to four dietary groups: normal diet (ND), 0.2% adenine diet (AD, CKD model), high-fat diet (HFD, metabolic model), and a combination of HFD+AD (potential CKM model).
• Mice underwent hind limb ischemia surgery.
• Evaluations included structural, endurance, and post-exercise hyperemia assays.

Main Results:

• Male mice on HFD+AD exhibited increased weight and GFR compared to the AD group, alongside kidney pathology (tubular atrophy, fibrosis, glomerulomegaly), hypercholesterolemia, impaired glucose tolerance, hepatic steatosis, and myocardial fibrosis.
• HFD+AD mice showed reduced hind limb perfusion, microcapillary density, and Type II muscle fibers, with increased muscle fibrosis and immune infiltration.
• Female CKM mice displayed distinct phenotypes, with additive effects on endurance but not post-ischemia perfusion, indicating skeletal muscle and microcapillary dysfunction.

Conclusions:

• The HFD+AD mouse model effectively displays features of chronic kidney disease (CKD), metabolic disorders, and cardiovascular disease at a higher GFR, aligning with human CKM.
• This model provides a valuable platform for exploring the complex mechanisms of CKM.
• The model highlights significant sex-specific differences in CKM phenotypes, crucial for understanding disease heterogeneity.