Kidney-Specific Klotho Gene Deletion Causes Aortic Aneurysm via Hyperphosphatemia.
Kidney-Specific Klotho Gene Deletion Causes Aortic Aneurysm via Hyperphosphatemia.
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DOI：
10.1161/hypertensionaha.121.17299
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Sun Z
中科院分区：
文献类型：
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作者：
Wang Q;Wang S;Sun Z
Klotho是一种抑制衰老的基因。本研究的目的是确定肾脏中klotho基因的缺失是否会导致主动脉瘤（AA），并探讨其潜在的机制。将KLflox -flox等位基因与他莫昔芬诱导的肾特异性CreERT2小鼠杂交，生成KLflox/flox；KspCadCreERT2老鼠。他莫昔芬注射诱导klotho基因的肾特异性缺失，导致正常饮食小鼠严重的高磷血症和胸部(T)和腹部(A) AA形成。Klotho消融后前7天主动脉壁结构破坏表现为主动脉细胞大量死亡和钙化，大量金属蛋白酶（MMP） 2/9分泌，弹性蛋白降解，胶原沉积有限，导致主动脉壁变薄和AA形成。随后7天主动脉的不良修复性重构表现为成纤维细胞的增殖和成骨分化，以及多余的胶原沉积，进一步促进主动脉壁增厚和AA进展。这些变化伴有主动脉巨噬细胞浸润和破骨细胞转移。有趣的是，低磷饮食使血清磷酸盐水平正常化，阻止血管细胞凋亡和成骨分化，从而保留klothoo缺陷小鼠的主动脉结构。在机制上，过量的无机磷酸盐和钙促进血管细胞的死亡、成骨分化和体内外MMP2/9的分泌。我们发现NF-kB介导的磷酸盐在体外诱导人主动脉平滑肌细胞产生MMP2。这些发现为Klotho缺陷引起的高磷血症在AA发展中的致病作用提供了第一个证据。膳食磷的干预控制可能是预防和治疗AA的新策略。
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 CreERT2 mice were crossed to generate KLflox/flox; KspCadCreERT2 mice. Tamoxifen injection induced kidney-specific deletion of klotho gene which led to severe hyperphosphatemia and thoracic (T) and abdominal (A) 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 metalloproteinase (MMP) 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-kB 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.