Abstract: FR-PO0285
Novel Experimental Model for Investigating Metabolic Changes in Cardiovascular-Kidney-Metabolic Syndrome
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Meister, Jaroslawna, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Mahajan, Shreya Yogesh, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Arifaj, Denada, Department of Nephrology, Faculty of Medicine, University Hospital, Heinrich Heine University, Duesseldorf, Germany
- Granata, Cesare, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Dürrschmidt, Olga, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Zivehe, Fariba, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Roden, Michael, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Jandeleit-Dahm, Karin, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- Stegbauer, Johannes, Department of Nephrology, Faculty of Medicine, University Hospital, Heinrich Heine University, Duesseldorf, Germany
Background
The Cardiovascular-Kidney-Metabolic (CKM) syndrome describes the stepwise development of cardiovascular (CV) complications, with hypertension, diabetes, and kidney disease as key risk factors from stage 2 onwards. While several drug classes show promising effects on CKM syndrome progression, their renal mechanisms of action remain poorly understood. Findings from preclinical and clinical studies underscore the importance of energy metabolism in renal and CV diseases and highlight the need for a deeper understanding of CKM pathophysiology to advance therapeutic strategies for the prevention and treatment of CKM.
Methods
We have generated a novel mouse model of CKM syndrome by subjecting 8-week-old db/db mice (T2D model) to a subtotal nephrectomy (sNx). Following metabolic in vivo characterization, renal cortex and heart were collected at study end for histology, citrate synthase activity (CSA) determination and ex vivo measurements of mitochondrial respiration using high-resolution respirometry. Carbachol-induced vasodilation was measured in aorta preparations, plasma cystatin C levels and albuminuria were measured as readouts of renal function and injury.
Results
Diabetic db/db mice exhibited glomerular hyperfiltration and microalbuminuria, representative of stage 2 CKM syndrome. Compared to sham-operated db/db mice, those subjected to sNx showed a 2-fold increase in plasma cystatin C levels, advanced albuminuria, increased expression of cardiac remodeling markers and an impaired carbachol-induced endothelial vasodilation, indicative of a stage 3 CKM syndrome with CV damage. CSA measurements suggested that mitochondrial content was reduced in the renal cortex, but remained unchanged in the heart of these mice. Interestingly, fatty acid-linked mitochondrial respiration was not affected in the renal cortex of diabetic mice with sNx, but decreased significantly in the heart compared to sham-operated db/db mice, reflecting a crosstalk between renal function decline and cardiac energy metabolism.
Conclusion
Our novel mouse model offers the opportunity to study pathophysiological mechanisms operating early in the development of the CKM syndrome and to test the effects of pharmacological and dietary interventions across various stages of the syndrome.