Chronic Hydroxychloroquine Improves Endothelial Dysfunction and Protects Kidney in a Mouse Model of Systemic Lupus Erythematosus

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2014-08, Vol.64 (2), p.330-337
• Main Authors: Gómez-Guzmán, Manuel, Jiménez, Rosario, Romero, Miguel, Sánchez, Manuel, Zarzuelo, María José, Gómez-Morales, Mercedes, O’Valle, Francisco, López-Farré, Antonio José, Algieri, Francesca, Gálvez, Julio, Pérez-Vizcaino, Francisco, Sabio, José Mario, Duarte, Juan
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - physiopathology; Acute Kidney Injury - prevention & control; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Disease Models, Animal; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Hydroxychloroquine - pharmacology; Hydroxychloroquine - therapeutic use; Hypertension - complications; Hypertension - drug therapy; Hypertension - physiopathology; Kidney - drug effects; Kidney - physiopathology; Kidneys; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - physiopathology; Medical sciences; Mice; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.114.03587

Hydroxychloroquine has been shown to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus. Hydroxychloroquine-treated lupus patients showed a lower incidence of thromboembolic disease. Endothelial dysfunction, the earliest indicator of the development of cardiovascular disease, is present in lupus. Whether hydroxychloroquine improves endothelial function in lupus is not clear. The aim of this study was to analyze the effects of hydroxychloroquine on hypertension, endothelial dysfunction, and renal injury in a female mouse model of lupus. NZBWF1 (lupus) and NZW/LacJ (control) mice were treated with hydroxychloroquine 10 mg/kg per day by oral gavage, or with tempol and apocynin in the drinking water, for 5 weeks. Hydroxychloroquine treatment did not alter lupus disease activity (assessed by plasma double-stranded DNA autoantibodies) but prevented hypertension, cardiac and renal hypertrophy, proteinuria, and renal injury in lupus mice. Aortae from lupus mice showed reduced endothelium-dependent vasodilator responses to acetylcholine and enhanced contraction to phenylephrine, which were normalized by hydroxychloroquine or antioxidant treatments. No differences among all experimental groups were found in both the relaxant responses to acetylcholine and the contractile responses to phenylephrine in rings incubated with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester. Vascular reactive oxygen species content and mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase subunits NOX-1 and p47 were increased in lupus mice and reduced by hydroxychloroquine or antioxidants. Chronic hydroxychloroquine treatment reduced hypertension, endothelial dysfunction, and organ damage in severe lupus mice, despite the persistent elevation of anti–double-stranded DNA, suggesting the involvement of new additional mechanisms to improve cardiovascular complications.