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Klotho Deficiency Causes Kidney Fibrosis via Activation of the Notch2 Signaling pathway
Author(s) -
Xu Yuechi,
Sun Zhongjie
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.663.15
Subject(s) - klotho , kidney , endocrinology , fibrosis , medicine , gene knockdown , biology , cancer research , gene , biochemistry
Background Klotho was originally identified as an aging‐suppressor gene. Mutation of Klotho gene causes severe kidney damage. In humans, chronic kidney disease is associated with diminished Klotho protein expression. The purpose of this study is to investigate molecular mechanism that mediates Klotho deficiency‐induced renal fibrosis. Methods & Results Trichrome staining showed that Klotho gene mutation enhanced tubular collagen deposition, indicating that Klotho deficiency caused kidney fibrosis. Interestingly, the Notch2 activity was increased significantly in kidneys of Klotho mutant mice, suggesting that Klotho may regulate Notch2 activity. Overexpression of Klotho suppressed Notch2 activity and decreased expression of fibrosis markers (smooth muscle actin and collagen I) in mouse kidney tubule cells. Knockdown of Notch2 also attenuated fibrosis markers. Therefore, Notch2 activation may mediate Klotho deficiency‐induced fibrosis formation. The functional interaction between Klotho and Notch2 was assessed by the lectin precipitate assay. Interestingly, the result showed that Klotho exhibited neuraminidase activity which inhibited Notch2 activity through removing α 2, 6 Neu5Ac from Notch2. A neuraminidase inhibitor (DANA) blocked the inhibitory effect Klotho on activation of Notch2. Conclusion Klotho deficiency‐induced renal fibrosis formation may be, at least in part, attributed to activation of Notch2. Klotho regulates Notch2 activity via its neuraminidase activity.