Generation of a novel murine model of cardiovascular-kidney metabolic syndrome
Embargo Date
2028-02-26
OA Version
Citation
Abstract
OBJECTIVE: Cardiovascular-kidney metabolic (CKM) syndrome refers to the collective interactions between metabolic dysfunction, cardiovascular disease (CVD), and chronic kidney disease (CKD). Emerging as a major threat to public health, CKM syndrome is prevalent in more than one in four adults within the US and is responsible for substantial mortality and healthcare burden. The mediators of CKM syndrome have yet to be fully elucidated due to a lack of reliable CKM models. Therefore, we set out to generate a model representing the pathophysiology of CKM syndrome.
METHODS: Twenty-eight male C57BL/6J mice were randomized into one of four casein-based diets administered for six weeks: normal diet (ND), 0.2% adenine-enriched diet (AD), 60% high-fat diet (HFD), and a combination of HFD + AD. PAD was induced via hindlimb ischemia as a downstream manifestation of CVD one week prior to diet randomization. Weekly GFR measurements were taken via FITC-Sinistrin clearance. Food intake, weight trends, and serum cholesterol and triglyceride levels were assessed. General (H&E, Picro-Sirius Red, Masson’s Trichrome) and IF (Adipophilin, a marker for non-alcoholic hepatic steatosis) staining was performed for histopathological analysis.
RESULTS: Compared to mice on AD, HFD + AD mice demonstrated an attenuated decline of GFR, yet manifested glomerulomegaly and tubulointerstitial fibrosis at a preserved GFR in a manner consistent with clinical CKM. Hypercholesterolemia, liver adipophilin expression, and sub-myocardial fibrosis were also observed in HFD + AD.
CONCLUSION: A combination of HFD + AD in mice manifests hallmarks of CKD (reduced GFR, renal fibrosis), metabolic dysfunction (dyslipidemia, glucose intolerance, non-alcoholic hepatic steatosis), and CVD (sub-myocardial fibrosis). The multiorgan phenotypes produced by this model may assist our mechanistic understanding of CKM syndrome and/or test therapeutic efficacy.
Description
2025
License
Attribution-NoDerivatives 4.0 International