title: Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis.
abstract: Renal expression of the klotho gene is markedly suppressed in chronic kidney disease (CKD). Since renal fibrosis is the final common pathology of CKD, we tested whether decreased Klotho expression is a cause and/or a result of renal fibrosis in mice and cultured renal cell lines. We induced renal fibrosis by unilateral ureteral obstruction (UUO) in mice with reduced Klotho expression (kl/+ mice) and compared them with wild-type mice. The UUO kidneys from kl/+ mice expressed significantly higher levels of fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin, and transforming growth factor-β(1) (TGF-β(1)) than those from wild-type mice. In addition, in cultured renal fibroblast cells (NRK49F), the levels of α-SMA and PAI1 expression were significantly suppressed by addition of recombinant Klotho protein to the medium. The similar effects were observed by a TGF-β(1) receptor inhibitor (ALK5 inhibitor). These observations suggest that low renal Klotho expression enhances TGF-β(1) activity and is a cause of renal fibrosis. On the other hand, TGF-β(1) reduced Klotho expression in renal cultured epithelial cells (inner medullary collecting duct and human renal proximal tubular epithelium), suggesting that low renal Klotho expression is a result of renal fibrosis. Taken together, renal fibrosis can trigger a deterioration spiral of Klotho expression, which may be involved in the pathophysiology of CKD progression.
authors.affiliation: Dept. of Medicine IV, Tokyo Women's Medical Univ., 8-1 Kawada-cho, Shinjuku-city, Tokyo, Japan 162-8666. sugiura@kc.twmu.ac.jp
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Sugiura
authors.forename: Takumi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Shunji
authors.initials: S
authors.lastname: Shiohira
authors.forename: Junko
authors.initials: J
authors.lastname: Kohei
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mitobe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurosu
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.forename: Kosaku
authors.initials: K
authors.lastname: Nitta
authors.forename: Ken
authors.initials: K
authors.lastname: Tsuchiya
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009395:Nephritis, Interstitial / Q000473:pathology / Q000503:physiopathology*; D051436:Renal Insufficiency, Chronic / Q000473:pathology / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D053773:Transforming Growth Factor beta1; D005966:Glucuronidase; D000090265:Klotho Proteins