Abstract: FR-OR038
Exosomes as Mediators of Cardiomyocyte Injury and Heart Failure in Experimental Glomerular Disease
Session Information
- Hypertension and Cardiorenal Disease: Novel Mechanisms and Therapeutic Targets
November 07, 2025 | Location: Room 332A, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Ray, Justina, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Raisinghani, Nikhil, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Santos-Gallego, Carlos G, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Wong, Jenny, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Li, Xisheng, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Sahoo, Susmita, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Campbell, Kirk N., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background
Cardiovascular (CV) disease is the leading cause of death in chronic kidney disease, and albuminuria is widely recognized as an independent risk factor for adverse cardiac outcomes. The molecular mechanisms linking albuminuria to CV disease, including heart failure, remain poorly understood partly due to a lack of preclinical models. The Hippo pathway- including LATS 1/2 kinases- is essential for podocyte homeostasis.
Methods
We generated a podocyte-specific LATS 1/2-knockout mouse line (PodLats-KO) using Nphs2-Cre. Kidney function and structure were assessed by BUN, serum creatinine, albuminuria, and histological analysis. Cardiac function and structure were assessed by cardiac MRI, serum biomarkers, IonOptix, histology, and bulk RNA sequencing.
Results
PodLats-KO mice developed albuminuria and focal segmental glomerulosclerosis (FSGS) by 5 weeks, with disease progression by 22 weeks. Despite preserved renal function and normal blood pressure, they died prematurely (median survival: 24.8 weeks). At 22 weeks, cardiac MRI revealed biventricular systolic dysfunction and cardiac hypertrophy. Left ventricular (LV) ejection fraction was 60.2% in WT and 43.1% in PodLats-KO (p<0.0001), and right ventricular ejection fraction was 71.6% in WT and 43.3% in PodLats-KO (p<0.0001). Telemetry monitoring demonstrated T-wave elevation preceding death, suggesting cardiac ischemia. At the cellular level, PodLats-KO cardiomyocytes showed reduced contractility, impaired calcium handling, oxidative stress, and apoptosis. RNA sequencing of LV tissue revealed broad transcriptional dysregulation, including downregulation of pathways critical to cardiac contraction.
To explore a mechanistic link, exosomes were isolated from WT and PodLats-KO kidneys. PodLats-KO kidney-derived exosomes were cardiotoxic to H9C2 cardiac myoblasts (p<0.05), caused impaired contractility in primary rat cardiomyocytes (p<0.001), and induced apoptosis following intramyocardial injection into healthy control LVs (p<0.01).
Conclusion
PodLats-KO mice develop FSGS with albuminuria, biventricular heart failure, and early cardiac death, providing an innovative model to explore molecular signaling between the kidney and heart in glomerular disease. Data suggest that kidney-derived exosomes may contribute to cardiomyocyte impairment and myocardial injury.
Funding
- NIDDK Support