Abstract | BACKGROUND: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH)2D3-generating 25-hydroxyvitamin D3 1-alpha-hydroxylase ( Cyp27b1) by FGF23. Conversely, 1,25(OH)2D3 stimulates, by activating the vitamin D3 receptor (Vdr), the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH)2D3 and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. METHODS: RESULTS: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours) and mice (8 hours or 5 days). Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours). Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. CONCLUSION:
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Authors | Ioana Alesutan, Martina Feger, Tatsiana Pakladok, Sobuj Mia, Mohamed Siyabeldin E Ahmed, Jakob Voelkl, Florian Lang |
Journal | Kidney & blood pressure research
(Kidney Blood Press Res)
Vol. 37
Issue 4-5
Pg. 475-87
( 2013)
ISSN: 1423-0143 [Electronic] Switzerland |
PMID | 24247665
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2013 S. Karger AG, Basel. |
Chemical References |
- FGF23 protein, human
- Fgf23 protein, mouse
- Spironolactone
- Fibroblast Growth Factor-23
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
- Glucuronidase
- Klotho Proteins
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Topics |
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
(physiology)
- Animals
- Female
- Fibroblast Growth Factor-23
- Gene Expression Regulation, Enzymologic
(drug effects)
- Glucuronidase
(biosynthesis, physiology)
- HEK293 Cells
- Humans
- Kidney
(drug effects, metabolism)
- Klotho Proteins
- Male
- Mice
- Mice, Inbred C57BL
- Spironolactone
(pharmacology)
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