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Arginine Dysregulation and Myocardial Dysfunction in a Mouse Model and Children with Chronic Kidney Disease
Loretta Z Reyes1,2, Pamela D Winterberg1,2, Roshan Punnoose George1,2
1Division of Pediatric Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Insights
Cardiovascular disease is a major risk in chronic kidney disease (CKD). Arginine metabolism is disrupted in CKD, contributing to heart dysfunction in both mice and children.
Area of Science:
- Nephrology
- Cardiology
- Biochemistry
Background:
- Cardiovascular disease (CVD) is the primary cause of mortality in patients with chronic kidney disease (CKD).
- Arginine, a crucial precursor for nitric oxide (NO) synthesis, plays a vital role in maintaining endothelial and myocardial function, and its production is significantly influenced by kidney function.
- Dysregulation of arginine bioavailability is implicated in the development of endothelial and myocardial dysfunction observed in CKD.
Purpose of the Study:
- To investigate the relationship between arginine metabolism, nitric oxide synthesis, and myocardial dysfunction in both a mouse model of CKD and in children with CKD.
- To evaluate the impact of arginase activity and asymmetric dimethylarginine (ADMA) on cardiovascular health in CKD patients.
Main Methods:
- Plasma samples from 129X1/SvJ mice (with and without 5/6th nephrectomy-induced CKD) and children (with and without CKD) were analyzed for amino acids, ADMA, and arginase activity.
- Echocardiography was used to assess myocardial function in mice, and these measures were correlated with plasma analytes.
- A non-specific arginase inhibitor was administered to mice with and without CKD to assess its therapeutic potential.
Main Results:
- Plasma citrulline and glutamine concentrations showed significant correlations with various measures of myocardial dysfunction in CKD.
- Arginase activity was significantly elevated in mice with CKD over time and in children undergoing dialysis compared to healthy controls.
- Ventricular strain improved in CKD mice following arginase inhibition, and increased ADMA levels correlated with increased relative wall thickness (RWT) in children with CKD.
Conclusions:
- Arginine dysregulation, characterized by altered arginase activity and ADMA levels, is closely linked to myocardial dysfunction in both a preclinical mouse model and human pediatric CKD patients.
- Targeting arginase activity may represent a potential therapeutic strategy for mitigating cardiovascular complications in CKD.
Abstract:
Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). Arginine, the endogenous precursor for nitric oxide synthesis, is produced in the kidneys. Arginine bioavailability contributes to endothelial and myocardial dysfunction in CKD. Plasma from 129X1/SvJ mice with and without CKD (5/6th nephrectomy), and banked plasma from children with and without CKD were analyzed for amino acids involved in arginine metabolism, ADMA, and arginase activity. Echocardiographic measures of myocardial function were compared with plasma analytes. In a separate experiment, a non-specific arginase inhibitor was administered to mice with and without CKD. Plasma citrulline and glutamine concentrations correlated with multiple measures of myocardial dysfunction. Plasma arginase activity was significantly increased in CKD mice at 16 weeks vs. 8 weeks (p = 0.002) and ventricular strain improved after arginase inhibition in mice with CKD (p = 0.03). In children on dialysis, arginase activity was significantly increased vs. healthy controls (p = 0.04). Increasing ADMA correlated with increasing RWT in children with CKD (r = 0.54; p = 0.003). In a mouse model, and children, with CKD, arginine dysregulation correlates with myocardial dysfunction.
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