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A novel mouse model for cardiovascular-kidney-metabolic syndrome: Bridging metabolic, renal and cardiac dysfunction
Arianne van Koppen1, José A Inia1, Romer A Gonzalez-Villalobos2
1Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
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.
Insights
A new mouse model combining uninephrectomy, high-fat diet, and L-NNA effectively mimics CKM syndrome, showing progressive kidney and heart failure. This model aids in studying obesity, type 2 diabetes, and related complications.
Area of Science:
- Nephrology
- Cardiology
- Metabolic Syndrome Research
Background:
- CKM syndrome encompasses obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), and cardiovascular disease (CVD).
- Existing preclinical models inadequately replicate the progressive renal and cardiac dysfunction seen in advanced CKM syndrome.
- This limits their utility for studying human disease progression and testing interventions.
Purpose of the Study:
- To develop and validate a preclinical model that accurately reproduces the key features of CKM syndrome.
- To investigate the combined effects of metabolic dysfunction and hypertension on renal and cardiac health.
- To establish a platform for mechanistic studies and therapeutic evaluations in CKM syndrome.
Main Methods:
- Male KK-Ay mice underwent uninephrectomy (UNx) and were fed a high-fat diet (HFD) for 13-16 weeks.
- The experimental group received the HFD with the vasoconstrictor L-NNA, while a control group received HFD alone.
- Renal function, cardiac function, histopathology, and transcriptomics were assessed.
Main Results:
- The UNx+HFD+L-NNA group exhibited obesity, hyperglycemia, and progressive kidney failure with significant glomerular damage and fibrosis.
- Renal transcriptomics revealed activated inflammatory and fibrotic pathways.
- Cardiac analysis indicated a phenotype of heart failure with preserved ejection fraction (HFpEF), characterized by altered cardiac dimensions and right ventricular fibrosis.
Conclusions:
- The UNx+HFD+L-NNA KK-Ay mouse model successfully replicates critical metabolic, renal, and cardiac aspects of CKM syndrome.
- Hypertension, induced by L-NNA, significantly worsens renal decline and cardiac remodeling alongside obesity and hyperglycemia.
- This validated model is suitable for mechanistic research and evaluating therapeutic strategies for CKM syndrome.
