Reduced klotho expression level in kidney aggravates renal interstitial fibrosis

Hidekazu Sugiura, Takumi Yoshida, Shunji Shiohira, Junko Kohei, Michihiro Mitobe, Hiroshi Kurosu, Makoto Kuro-O, Kosaku Nitta, Ken Tsuchiya

Research output: Contribution to journalArticle

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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-β1 (TGF-β1) 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-β1 receptor inhibitor (ALK5 inhibitor). These observations suggest that low renal Klotho expression enhances TGF-β1 activity and is a cause of renal fibrosis. On the other hand, TGF-β1 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number10
DOIs
StatePublished - May 15 2012

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Fibrosis
Kidney
Transforming Growth Factors
Chronic Renal Insufficiency
Ureteral Obstruction
Cultured Cells
Growth Factor Receptors
Fibronectins
Recombinant Proteins
Smooth Muscle
Disease Progression
Actins
Epithelium
Fibroblasts
Epithelial Cells
Pathology
Gene Expression
Cell Line

Keywords

  • Chronic kidney disease
  • Renal tubular epithelial cells
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Reduced klotho expression level in kidney aggravates renal interstitial fibrosis. / Sugiura, Hidekazu; Yoshida, Takumi; Shiohira, Shunji; Kohei, Junko; Mitobe, Michihiro; Kurosu, Hiroshi; Kuro-O, Makoto; Nitta, Kosaku; Tsuchiya, Ken.

In: American Journal of Physiology - Renal Physiology, Vol. 302, No. 10, 15.05.2012.

Research output: Contribution to journalArticle

Sugiura, H, Yoshida, T, Shiohira, S, Kohei, J, Mitobe, M, Kurosu, H, Kuro-O, M, Nitta, K & Tsuchiya, K 2012, 'Reduced klotho expression level in kidney aggravates renal interstitial fibrosis', American Journal of Physiology - Renal Physiology, vol. 302, no. 10. https://doi.org/10.1152/ajprenal.00294.2011
Sugiura, Hidekazu ; Yoshida, Takumi ; Shiohira, Shunji ; Kohei, Junko ; Mitobe, Michihiro ; Kurosu, Hiroshi ; Kuro-O, Makoto ; Nitta, Kosaku ; Tsuchiya, Ken. / Reduced klotho expression level in kidney aggravates renal interstitial fibrosis. In: American Journal of Physiology - Renal Physiology. 2012 ; Vol. 302, No. 10.
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