Arginine Dysregulation and Myocardial Dysfunction in a Mouse Model and Children with Chronic Kidney Disease

Figures

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  Figure 1. Arginine biosynthetic pathways De novo arginine synthesis occurs in the proximal tubules of the kidneys from citrulline. Arginine is the substrate for both nitric oxide synthase and arginase enzymes. Global arginine bioavailability ratio (GABR) reflects substrate availability for nitric oxide synthesis. Abbreviations: GFR, glomerular filtration rate; ADMA, asymmetric dimethylarginine.

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  Figure 2. Dysregulated amino acid metabolism correlates with myocardial dysfunction in mice with and without CKD (n = 35). In mice with and without CKD, higher plasma citrulline concentration correlates with LVH (A), diastolic dysfunction (B), and impaired myocardial strain (C); reduced GABR correlates with LVH (D), diastolic dysfunction (E), but not with stain (F); reduced plasma glutamine concentration correlates with LVH (G), diastolic dysfunction (H), and impaired myocardial strain (I). Abbreviations: GABR, global arginine bioavailability ratio; RWT, relative wall thickness; CKD, chronic kidney disease; GLS, global longitudinal strain. Note: sample sizes may differ due to varying missingness in amino acid concentration and/or echo data.

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  Figure 3. Plasma arginase activity correlates with myocardial dysfunction in mice with and without CKD (n = 35). In mice with CKD, plasma arginase activity is increased at 16 weeks compared to 8 weeks (A); no correlation between plasma arginase activity and LVH as measured by RWT in mice with and without CKD (B); a trending correlation is identified between plasma arginase activity and diastolic dysfunction as measured by E/A ratio in mice with and without CKD (C); plasma arginase activity correlates with impaired myocardial strain as measured by GLS in mice with and without CKD (D). Abbreviations: GABR, global arginine bioavailability ratio; RWT, relative wall thickness; CKD, chronic kidney disease; GLS, global longitudinal strain. Note: sample sizes may differ due to varying missingness in arginase activity and/or echo data.

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  Figure 4. Arginase inhibition with CB-280 improves GLS in mice with CKD (n = 10). In mice with and without CKD, arginase inhibition via CB-280 restored impaired myocardial straI (C), but no effect on LVH (A) or diastolic function (B). Abbreviations: RWT, relative wall thickness; GLS, global longitudinal strain; Tx, treatment.