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Low Phosphate Diet Prevents Klotho Deficiency‐induced Aortic Aneurysm
Author(s) -
Wang Qiongxin,
Lin Yi,
Ali Quaisar,
Sun Zhongjie
Publication year - 2017
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.31.1_supplement.875.9
Subject(s) - klotho , hyperphosphatemia , endocrinology , medicine , vascular smooth muscle , knockout mouse , kidney , chemistry , kidney disease , receptor , smooth muscle
Background Mutation of Klotho gene causes aberrant mineral metabolism characterized by severe hyperphosphatemia and hypercalceamia and early death. However, the causative link between klotho deficiency and aortic aneurysm (AA) is unknown. Methods and Results Klotho‐floxed alleles (Klotho flox/flox ) and transgenic tamoxifen‐inducible kidney specific CreER T2 mice were crossed to generate double‐transgenic mice (klotho flox/flox ; KspCad CreER T2 +/−). Tamoxifen (60 mg/kg/day, IP, for a total of 5 consecutive days) was given to induce kidney‐specific deletion of klotho gene. The aortas were intact in the control mice, whereas the thoracic and abdominal AA were observed in all the klotho knockout mice (100% incidence) on normal diet (ND) which suffered hyperphosphatemia and hypertension after 15 days of tamoxifen‐induced gene deletion. The histological staining exhibited severe aortic destruction in klotho knockout mice on ND, including aortic calcification and expansion, elastin degradation, collagen deposition and the absence of vascular smooth muscle cells (VSMCs) (residues <5%) substituted by macrophages and osteoclasts. Moreover, significantly increased expression and activity of matrix metallopeptidase (MMP) 2 and 9 were detected in the aortas of klotho knockout mice on ND compared to control mice. However, low phosphate diet (LPD) aattenuated hyperphosphatemia, hypertension, structure damage of aortas, and resultant AA formation by klotho deficiency. In cultured mouse vascular aortic smooth muscle cells (MOVAS), inorganic phosphate and calcium intensively induced osteoblast transition, MMP2 secretion and cell death by upregulating RUNX2, CREB phosphorylation and cleavage of caspase 3. Conclusions We conclude that klotho deficiency instigates AA formation through hyperphosphatemia‐driven aortic calcification and elastin degradation.