title: Indoxyl sulfate reduces klotho expression and promotes senescence in the kidneys of hypertensive rats.
abstract: BACKGROUND
  Administration of indoxyl sulfate, a uremic toxin, promotes progression of chronic kidney disease in rats affected by the disease. Klotho, an anti-aging gene, is expressed in the kidneys, and its renal expression is decreased in chronic kidney disease. This study aimed to clarify whether indoxyl sulfate could reduce klotho expression and contribute to cell senescence in the kidneys of hypertensive rats.
  
  
  METHODS
  The rats used for this study were segregated in to the following 4 groups: (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 32 weeks, their kidneys were excised for histological and immunohistochemical analysis for klotho, senescence-associated β-galactosidase, p16(INK4a), p21(WAF1/CIP1), p53, and retinoblastoma protein (Rb).
  
  
  RESULTS
  DH + IS rats showed decreased expression of klotho, increased expression of senescence-associated β-galactosidase, p16(INK4a), p21(WAF1/CIP1), p53, and Rb in renal tubular cells, and increased tubulointerstitial fibrosis and mesangial expansion as compared with DH rats. Further, DN + IS rats showed decreased expression of klotho as compared with DN rats.
  
  
  CONCLUSIONS
  Administration of indoxyl sulfate to hypertensive rats reduced renal expression of klotho and promoted cell senescence with expression of senescence-related proteins, such as p16(INK4a), p21(WAF1/CIP1), p53, and Rb, which was accompanied by renal fibrosis.
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan.
authors.forename: Ayinuer
authors.initials: A
authors.lastname: Adijiang
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Shimizu
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Nishijima
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016922:Cellular Senescence; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology*; D007200:Indican / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D051381:Rats; D020303:Rats, Inbred Dahl; D016160:Retinoblastoma Protein / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D001616:beta-Galactosidase; D005966:Glucuronidase; D000090265:Klotho Proteins; D007200:Indican