Reduced endothelial nitric oxide synthase activation contributes to cardiovascular injury during chronic kidney disease progression

• Published in: American journal of physiology. Renal physiology Vol. 317; no. 2; pp. F275 - F285
• Main Authors: Amador-Martínez, Isabel, Pérez-Villalva, Rosalba, Uribe, Norma, Cortés-González, César, Bobadilla, Norma A, Barrera-Chimal, Jonatan
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2019
• Subjects: Acute Kidney Injury - complications; Acute Kidney Injury - drug therapy; Acute Kidney Injury - enzymology; Animals; Arginine; Arginine - pharmacology; Bioavailability; Brain natriuretic peptide; Cardiomegaly - enzymology; Cardiomegaly - etiology; Cardiomegaly - prevention & control; Dimerization; Disease Models, Animal; Disease Progression; Down-Regulation; Enzyme Activation; Fibrosis; Heart; Heat shock proteins; HSP90 Heat-Shock Proteins - metabolism; Hypertrophy; Ischemia; Kidney diseases; Male; Myocardium - enzymology; Natriuretic Peptide, Brain - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Oxidative Stress; Peptides; Phosphorylation; Proteinuria; Rats, Wistar; Renal function; Renal Insufficiency, Chronic - enzymology; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - prevention & control; Reperfusion; Rodents; Surgery; Threonine; Time Factors; endothelial nitric oxide synthase; cardiorenal; nitric oxide; arginine; asymmetric dimethyl-arginine; heat shock protein 90
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00020.2019

Major cardiovascular events are a common complication in patients with chronic kidney disease (CKD). Endothelial dysfunction can contribute to the cardiovascular injury observed in CKD. Here, we used a rat model of acute kidney injury to CKD transition to investigate heart alterations in the pathway activating endothelial nitric oxide synthase (eNOS) and its impact on the cardiac injury observed during CKD progression. Fifty male Wistar rats were subjected to sham surgery ( = 25) or bilateral renal ischemia-reperfusion (IR-CKD) for 45 min ( = 25). Rats were studied on a monthly basis up to 5 mo ( = 5). In another set of sham and IR-CKD rats, l-arginine was administered starting on the third month after renal ischemia. CKD development and cardiac alterations were monitored in all groups. CKD was characterized by a progressive increase in proteinuria and renal dysfunction that was evident after the fifth month of followup. Heart hypertrophy was observed starting on the fourth month after ischemia-reperfusion. There was a significant increase in brain natriuretic peptide levels. In the heart, IR-CKD rats had increased eNOS phosphorylation at threonine 495 and reduced eNOS-heat shock protein-90α interactions. l-Arginine administration prevented the heart alterations observed during CKD and increased eNOS coupling/dimerization and activation. In summary, CKD progression is accompanied by cardiac hypertrophy, fibrosis, oxidative stress, and increased brain natriuretic peptide levels. These alterations were associated with limited eNOS activation in the heart, which may result in reduced nitric oxide bioavailability and contribute to cardiac injury during CKD.