Kidney-Specific Klotho Gene Deletion Causes Aortic Aneurysm via Hyperphosphatemia

Klotho is an aging-suppressor gene. The purpose of this study was to determine whether deletion of the klotho gene in kidneys causes aortic aneurysm (AA) and investigate the underlying mechanisms. Klotho-floxed alleles and tamoxifen-inducible kidney-specific CreER T2 mice were crossed to generate KL flox/flox (floxed Klotho); KspCadCreER T2 mice. Tamoxifen injection induced kidney-specific deletion of klotho gene, which led to severe hyperphosphatemia and thoracic and abdominal AA formation in mice on a normal diet. The architectural destruction of the aortic wall in the first 7 days post-Klotho ablation was manifested by overwhelming aortic cell death and calcification, massive MMP (metalloproteinase) 2/9 secretion, elastin degradation, and limited collagen deposition, resulting in aortic wall thinning and AA formation. The adverse reparative remodeling of aortas in the following 7 days exhibited robust fibroblast proliferation and osteogenic differentiation and redundant collagen deposition, further promoting aortic wall thickening and AA progression. These changes were accompanied by aortic macrophage infiltration and osteoclast transition. Interestingly, low-phosphorus diet normalized serum phosphate levels, prevented vascular cell apoptosis and osteogenic differentiation, and consequently retained aortic structure in Klotho-deficient mice. Mechanistically, excessive inorganic phosphate and calcium promoted vascular cell death, osteogenic differentiation, and MMP2/9 secretion ex vivo and in vitro. We found that NF-κB (nuclear factor-kappa B) mediated phosphate-induced MMP2 generation in human aortic smooth muscle cells in vitro. These findings provide the first evidence for a causative role of Klotho deficiency–induced hyperphosphatemia in AA development. Interventional control of dietary phosphorus may be a new preventive and therapeutic strategy for AA.