A novel mouse model for cardiovascular-kidney-metabolic syndrome: Bridging metabolic, renal and cardiac dysfunction
Year: 2026
Type: article
Abstract: BACKGROUND: CKM syndrome involves obesity, type 2 diabetes (T2D), chronic kidney disease (CKD) and cardiovascular disease (CVD). However, most preclinical models fail to reproduce the progressive renal and cardiac dysfunction characteristic of advanced CKM syndrome, limiting their ability to accurately reflect human disease. METHODS: Male uninephrectomized (UNx) KK-Ay mice received a high-fat diet (HFD) with or without the vasoconstrictor L-NNA for 13-16 weeks. RESULTS: UNx + HFD + L-NNA resulted in obesity, hyperglycemia and progressive kidney failure, indicated by a rapid increase in albuminuria and transient hyperfiltration followed by progressive glomerular filtration rate (GFR) decline over three months. Histopathological analysis revealed severe glomerular damage, fibrosis, inflammation and basement membrane thickening, most pronounced in UNx + HFD + L-NNA mice. Renal transcriptomics analysis revealed robust activation of inflammatory and fibrotic pathways, again most pronounced in UNx + HFD + L-NNA mice. In the heart, UNx + HFD + L-NNA resulted in increased ejection fraction and fractional shortening, reduced end-systolic volume and increased left ventricular posterior wall thickness. Alongside pronounced right ventricular fibrosis, this phenotype points toward a phenotype of heart failure with preserved ejection fraction (HFpEF). CONCLUSIONS: The UNx + HFD + L-NNA KK-Ay model reproduces key metabolic, renal and cardiac components of CKM syndrome. While obesity and hyperglycemia contribute substantially to disease burden, L-NNA-induced hypertension further exacerbates both renal decline and cardiac remodeling. Therefore, this model enables mechanistic investigation and evaluation of therapeutic strategies for CKM syndrome.
Source: Molecular Metabolism
Authors: Arianne van Koppen, José A. Inia, Romer A. Gonzalez-Villalobos, Anke M. Smits, Andrea R. Nawrocki, Simon A. Hinke, Joline Attema, Christa de Ruiter, Tri Q. Nguyen, Amelie Dendooven, Ingeborg Bajema, Harry van Goor, Toon A.B. van Veen, Willem B. van Ham, Felix Eichinger, Søren H. Elsborg, Henricus A.M. Mutsaers, Elsbet J. Pieterman, Aswin L. Menke, Matthew D. Breyer, Reinout Stoop
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funder: Health~Holland
OpenAlex ID: W7155000241