Spironolactone ameliorates arterial medial calcification in uremic rats: the role of mineralocorticoid receptor signaling in vascular calcification

• Published in: American journal of physiology. Renal physiology 2015-12, Vol.309 (11), p.F967-F979
• Main Authors: Tatsumoto, Narihito, Yamada, Shunsuke, Tokumoto, Masanori, Eriguchi, Masahiro, Noguchi, Hideko, Torisu, Kumiko, Tsuruya, Kazuhiko, Kitazono, Takanari
• Format: Article
• Language: English
• Subjects: Adenine; Animals; Aorta, Abdominal - drug effects; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aortic Diseases - blood; Aortic Diseases - chemically induced; Aortic Diseases - pathology; Aortic Diseases - physiopathology; Aortic Diseases - prevention & control; Apoptosis; Apoptosis - drug effects; Biomarkers - blood; Blood pressure; Calcification; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Humans; Hyperphosphatemia - blood; Hyperphosphatemia - drug therapy; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Male; Mineralocorticoid Receptor Antagonists - pharmacology; Osteogenesis - drug effects; Oxidative stress; Rats, Sprague-Dawley; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - metabolism; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - chemically induced; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - physiopathology; Renin-Angiotensin System - drug effects; Rodents; Signal transduction; Signal Transduction - drug effects; Spironolactone - pharmacology; Time Factors; Tunica Media - drug effects; Tunica Media - metabolism; Tunica Media - pathology; Uremia - blood; Uremia - chemically induced; Uremia - drug therapy; Uremia - pathology; Uremia - physiopathology; Vascular Calcification - blood; Vascular Calcification - chemically induced; Vascular Calcification - pathology; Vascular Calcification - physiopathology; Vascular Calcification - prevention & control
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00669.2014

Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control group and four groups of rats with adenine-induced CKD. Three groups were treated with 0, 50, and 100 mg·kg(-1)·day(-1) SPL for 8 wk, and one group was treated with 100 mg·kg(-1)·day(-1) SPL for the last 2 wk of the 8-wk treatment period. After 8 wk, CKD rats developed azotemia and hyperphosphatemia, with increases in the expression of serum and glucocorticoid-regulated kinase-1 and sodium-phosphate cotransporter, in inflammation and oxidative stress level, in osteogenic signaling and apoptosis, and in aortic calcification, compared with control rats. SPL dose dependently decreased these changes in the aortas, concomitant with improvements in renal inflammation, tubulointerstitial nephritis, and kidney function. SPL neither lowered blood pressure level nor induced hyperkalemia. Treatment of CKD rats for the last 2 wk with 100 mg·kg(-1)·day(-1) SPL attenuated VC compared with CKD rats with the same degree of kidney function and hyperphosphatemia. In conclusion, SPL dose dependently inhibits the progression of VC by suppressing MR signaling, local inflammation, osteogenic transition, and apoptosis in the aortas of CKD rats.