Evidence mapPaperPMID 42019921Full record

ArticleMolecular metabolism2026

A novel mouse model for cardiovascular-kidney-metabolic syndrome: Bridging metabolic, renal and cardiac dysfunction.

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 and 11 more

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Article in Molecular metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

21 authors.

Arianne van KoppenDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands. Electronic address: arianne.vankoppen@tno.nl.
José A IniaDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
Romer A Gonzalez-VillalobosJohnson & Johnson Innovative Medicine, Cambridge, MA, United States of America.
Anke M SmitsDepartment of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Andrea R NawrockiJohnson & Johnson Innovative Medicine, Cambridge, MA, United States of America.
Simon A HinkeJohnson & Johnson Innovative Medicine, Cambridge, MA, United States of America.
Joline AttemaDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
Christa de RuiterDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
Tri Q NguyenDepartment of Pathology, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
Amelie DendoovenDepartment of Pathology, University Medical Center Antwerp, Antwerp, Belgium.
Ingeborg BajemaDepartment of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
Harry van GoorDepartment of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
Toon A B van VeenDepartment of Medical Physiology, UMCU, the Netherlands.
Willem B van HamDepartment of Medical Physiology, UMCU, the Netherlands.
Felix EichingerDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, United States of America.
Søren H ElsborgDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Henricus A M MutsaersDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Elsbet J PietermanDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
Aswin L MenkeDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
Matthew D BreyerJohnson & Johnson Innovative Medicine, Cambridge, MA, United States of America.
Reinout StoopDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCKM 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.

methodsMale uninephrectomized (UNx) KK-Ay mice received a high-fat diet (HFD) with or without the vasoconstrictor L-NNA for 13-16 weeks.

resultsUNx + 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).

conclusionsThe 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.

Indexed as

Cardio-Renal SyndromeCardiovascular DiseasesMetabolic SyndromeAnimalsDiet, High-FatDisease Models, AnimalFibrosisGlomerular Filtration RateKidneyMaleMiceObesityCardiovascular-kidney-metabolic syndromeGFR declineGlomerulosclerosisHFpEFProgressive diabetic kidney disease

Identifiers

PMID42019921
PMCPMC13145895

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.