NDT Advance Access originally published online on March 11, 2008
Nephrology Dialysis Transplantation 2008 23(6):1892-1901; doi:10.1093/ndt/gfm861
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats
1 Department of Clinical Preventive Medicine, Nagoya University Hospital, Nagoya, Japan 2 Biomedical Research Laboratories, Kureha Co., Tokyo, Japan
Correspondence and offprint requests to: Correspondence and offprint request to: Toshimitsu Niwa, MD, PhD, Nagoya University Hospital, Department of Clinical Preventive Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. Tel: +81-52-744-1980; Fax: +81-52-744-1954; Email: tniwa{at}med.nagoya-u.ac.jp
 |
Abstract |
|---|
Background. Stage 5 chronic kidney disease (CKD) is associated with enhanced aortic calcification. The aim of this study was to determine if the administration of indoxyl sulphate (IS), a uraemic toxin, stimulates the progression of aortic calcification.
Methods. The rat groups consisted of (i) Dahl salt-resistant normotensive rats (DR) with intake of 0.3% salt, (ii) Dahl salt-sensitive hypertensive rats (DS) with intake of 2.0% salt and (iii) Dahl salt-sensitive hypertensive IS-administered rats (DS-IS) with intake of 2.0% salt and 200 mg/kg of IS in water. After 30 weeks, their aortic and kidney tissues were excised for histological and immunohistochemical analyses.
Results. Severe vascular calcification was observed by von Kossa staining in the arcuate aorta of all the DS-IS rats, but hardly in DS or DR rats. Immunohistochemistry demonstrated that osteopontin, core binding factor 1 (Cbfal), alkaline phosphatase (ALP), osteocalcin, IS and organic anion transporter (OAT) 3 were colocalized in the cells embedded in the aortic calcification area of DS-IS rats. Wall thickness was significantly increased in arcuate, thoracic and abdominal aortas of DS-IS rats compared with DS and DR rats. DS-IS rats showed significantly increased extent of glomerular hypertrophy, mesangial expansion, Masson's trichrome-positive tubulointerstitial area and glomerular and tubulointerstitial expression of transforming growth factor-ßl as compared with DS and DR rats.
Conclusions. IS induced aortic calcification with expression of osteoblast-specific proteins and aortic wall thickening. IS is not only a nephrotoxin but also a vascular toxin, and may contribute to the progression of aortic calcification in stage 5 CKD patients.
Keywords: aortic calcification; indoxyl sulphate; organic anion transporter; osteopontin; uraemic toxin
Received for publication: 27. 5.07
Accepted in revised form: 14.11.07