Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression
Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression
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DOI：
10.1385/endo:25:3:229
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发表时间：
2004-12-01
期刊：
影响因子：
3.7
通讯作者：
Ogihara, T
中科院分区：
文献类型：
--
作者：
Imai, M;Ishikawa, K;Ogihara, T
纯合子Klotho突变（kI（-/-））小鼠表现出多种类似人类衰老的表型，包括动脉硬化、不育、皮肤萎缩、骨质疏松和寿命短。钙异常是kI（-/-）小鼠的表型之一，被认为是由于肾脏中25-羟维生素D，1 α-羟化酶基因表达升高所致。我们研究了25-羟基维生素D-3 Ia-羟化酶基因的表达，使用Klotho质粒，我们以前构建的Klotho蛋白生产。发现Klotho蛋白培养基上调肾细胞中的cAMP和PKC途径，并抑制25-羟基维生素D-3 1 α-羟化酶。然而，已知cAMP和PKC都能提高25-羟基维生素D3 1 α-羟化酶基因的表达，因此，可能存在另一种未知的使用Klotho蛋白培养基的钙调节途径。此外，我们发现Klotho激活PKC途径仅在Klotho基因表达的肾脏和睾丸中观察到，尽管在任何类型的细胞中观察到cAMP途径的激活。这些数据表明Klotho通过25-羟基维生素D-3 1 α-羟化酶进行的钙调节依赖于非cAMP和非PKC途径，并且Klotho蛋白可能具有不同的信号传导途径，这取决于Klotho基因在不同细胞和器官中的表达。
Homozygous Klotho mutant (kI(-/-)) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kI(-/-) mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D, 1 a-hydroxylase in the kidney. We studied 25-hydroxyvitamin D-3 la-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho protein production. It was found that Klotho protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D-3 1 alpha-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1 alpha-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D-3 1 alpha-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.