Saar-Kovrov Valeria, Donners Marjo M P C, van der Vorst Emiel P C
Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands.
Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
Front Cardiovasc Med. 2021 Jan 28;7:617842. doi: 10.3389/fcvm.2020.617842. eCollection 2020.
α-Klotho (Klotho) exists in two different forms, a membrane-bound and soluble form, which are highly expressed in the kidney. Both forms play an important role in various physiological and pathophysiological processes. Recently, it has been identified that soluble Klotho arises exclusively from shedding or proteolytic cleavage. In this review, we will highlight the mechanisms underlying the shedding of Klotho and the functional effects of soluble Klotho, especially in CKD and the associated cardiovascular complications. Klotho can be cleaved by a process called shedding, releasing the ectodomain of the transmembrane protein. A disintegrin and metalloproteases ADAM10 and ADAM17 have been demonstrated to be mainly responsible for this shedding, resulting in either full-length fragments or sub-fragments called KL1 and KL2. Reduced levels of soluble Klotho have been associated with kidney disease, especially chronic kidney disease (CKD). In line with a protective effect of soluble Klotho in vascular function and calcification, CKD and the reduced levels of soluble Klotho herein are associated with cardiovascular complications. Interestingly, although it has been demonstrated that soluble Klotho has a multitude of effects its direct impact on vascular cells and the exact underlying mechanisms remain largely unknown and should therefore be a major focus of further research. Moreover, functional implications of the cleavage process resulting in KL1 and KL2 fragments remain to be elucidated.
α-klotho（Klotho）以两种不同形式存在，即膜结合形式和可溶性形式，在肾脏中高度表达。这两种形式在各种生理和病理生理过程中都发挥着重要作用。最近，已确定可溶性Klotho仅来源于脱落或蛋白水解切割。在本综述中，我们将重点介绍Klotho脱落的潜在机制以及可溶性Klotho的功能作用，特别是在慢性肾脏病（CKD）及其相关心血管并发症方面。Klotho可通过一种称为脱落的过程被切割，释放跨膜蛋白的胞外结构域。已证明一种去整合素和金属蛋白酶ADAM10和ADAM17主要负责这种脱落，产生全长片段或称为KL1和KL2的亚片段。可溶性Klotho水平降低与肾脏疾病有关，尤其是慢性肾脏病（CKD）。与可溶性Klotho对血管功能和钙化的保护作用一致，CKD以及本文中可溶性Klotho水平降低与心血管并发症有关。有趣的是，尽管已证明可溶性Klotho有多种作用，但其对血管细胞的直接影响以及确切的潜在机制在很大程度上仍不清楚，因此应成为进一步研究的主要重点。此外，导致KL1和KL2片段的切割过程的功能意义仍有待阐明。
