Spironolactone ameliorates arterial medial calcification in uremic rats: the role of mineralocorticoid receptor signaling in vascular calcification.
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.
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Narihito
N
Tatsumoto
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
Shunsuke
S
Yamada
Division of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
Masanori
M
Tokumoto
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Masahiro
M
Eriguchi
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Hideko
H
Noguchi
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Kumiko
K
Torisu
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and tsuruya@intmed2.med.kyushu-u.ac.jp.
Kazuhiko
K
Tsuruya
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Takanari
T
Kitazono
D000225:Adenine; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054559:Hyperphosphatemia / Q000097:blood / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D010012:Osteogenesis / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors; D017540:Tunica Media / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014511:Uremia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D061205:Vascular Calcification / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000225:Adenine
chronic kidney disease; hyperphosphatemia; mineralocorticoid receptor; spironolactone; vascular calcification