Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats.
We demonstrated that administration of indoxyl sulfate, a uremic toxin, promotes aortic calcification in hypertensive rats. This study aimed to clarify if indoxyl sulfate could contribute to cell senescence in the aorta of hypertensive rats. The rat groups consisted of (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). After 32weeks, their arcuate aortas were excised for histological and immunohistochemical analysis. Cell senescence was evaluated by immunohistochemistry of senescence-associated beta-galactosidase (SA-beta-gal), and senescence-related proteins such as p16(INK4a), p21(WAF1/CIP1), p53 and retinoblastoma protein (Rb). Both DH and DH+IS rats showed significantly higher systolic blood pressure than DN and DN+IS rats, respectively. Serum indoxyl sulfate levels were significantly higher in DN+IS and DH+IS rats than in DN and DH rats, respectively. In aorta, DH rats showed significantly increased aortic calcification and wall thickness, and increased expression of SA-beta-gal, p16(INK4a), p21(WAF1/CIP1), p53 and Rb in the calcification area of arcuate aorta as compared with DN rats. More notably, DH+IS rats showed significantly increased aortic calcification and wall thickness, and significantly increased expression of SA-beta-gal, p16(INK4a), p21(WAF1/CIP1), p53 and Rb in the cells embedded in the calcification area as compared with DH rats. In conclusion, indoxyl sulfate promotes cell senescence with aortic calcification and expression of senescence-related proteins in hypertensive rats.
Adijiang
Ayinuer
A
Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Higuchi
Yusuke
Y
Nishijima
Fuyuhiko
F
Shimizu
Hidehisa
H
Niwa
Toshimitsu
T
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001018:Aortic Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002114:Calcinosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism / Q000473:pathology*; D007200:Indican / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D020303:Rats, Inbred Dahl; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014511:Uremia / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
C493958:Cdkn1a protein, rat; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; D007200:Indican