Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain.
Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Sci Rep. 2023 Mar 14;13(1):4211. doi: 10.1038/s41598-023-31117-6.
The aging-protective gene α-Klotho (KL) produces two main transcripts. The full-length mRNA generates a transmembrane protein that after proteolytic ectodomain shedding can be detected in serum as processed Klotho (p-KL), and a shorter transcript which codes for a putatively secreted protein (s-KL). Both isoforms exhibit potent pleiotropic beneficial properties, although previous reports showed negative side effects on mineral homeostasis after increasing p-KL concentration exogenously. Here, we expressed independently both isoforms using gene transfer vectors, to assess s-KL effects on mineral metabolism. While mice treated with p-KL presented altered expression of several kidney ion channels, as well as altered levels of P and Ca in blood, s-KL treated mice had levels comparable to Null-treated control mice. Besides, bone gene expression of Fgf23 showed a fourfold increase after p-KL treatment, effects not observed with the s-KL isoform. Similarly, bone microstructure parameters of p-KL-treated mice were significantly worse than in control animals, while this was not observed for s-KL, which showed an unexpected increase in trabecular thickness and cortical mineral density. As a conclusion, s-KL (but not p-KL) is a safe therapeutic strategy to exploit KL anti-aging protective effects, presenting no apparent negative effects over mineral metabolism and bone microstructure.
衰老保护基因α-Klotho（KL）产生两种主要的转录本。全长 mRNA 生成一种跨膜蛋白，该蛋白在蛋白水解后可在血清中检测到，被称为处理 Klotho（p-KL），而较短的转录本则编码一种假定分泌的蛋白（s-KL）。这两种同工型都具有强大的多效有益特性，尽管之前的报告显示，在外源性增加 p-KL 浓度后，对矿物质稳态有负面影响。在这里，我们使用基因转移载体独立表达这两种同工型，以评估 s-KL 对矿物质代谢的影响。虽然用 p-KL 处理的小鼠表现出肾脏离子通道的几种表达改变，以及血液中 P 和 Ca 水平的改变，但用 s-KL 处理的小鼠的水平与 Null 处理的对照小鼠相当。此外，Fgf23 的骨基因表达在 p-KL 处理后增加了四倍，而 s-KL 同工型则没有观察到这种效果。同样，p-KL 处理小鼠的骨微观结构参数明显比对照动物差，而 s-KL 则没有观察到这种情况，s-KL 反而出乎意料地增加了小梁厚度和皮质矿物质密度。总之，s-KL（而不是 p-KL）是一种安全的治疗策略，可以利用 KL 的抗衰老保护作用，对矿物质代谢和骨微观结构没有明显的负面影响。
