Shedding of Klotho: Functional Implications in Chronic Kidney Disease and Associated Vascular Disease

Abstract

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.

Keywords: Klotho; a disintegrin and metalloprotease; chronic kidney disease; ectodomain shedding; vascular disease.

Figure 1

Schematic overview of Klotho structure and cleavage. Membrane-bound Klotho consists of four main domains, being the signal sequence (SS), KL1, KL2, and the transmembrane domain (TM). Several sheddases can cut this membrane-bound Klotho forming full-length soluble Klotho (α-cut) or KL1 and KL2 soluble Klotho (both α- and β-cut). Illustrated sequences reflect the suggested cleavage sites at which these cuts occur. Figure is created with BioRender.com.

Figure 2

Local and systemic effects of soluble Klotho. Klotho is mainly expressed in the kidney where it interacts with FGF23 to regulate phosphate levels. By changing phosphate levels, Klotho for example has an effect on vascular calcification and possibly also on the heart. Additionally, Klotho is shed by shedding enzymes (e.g., ADAM10/ADAM17) generating soluble Klotho, either full-length or subfragment KL1 and KL2. Soluble Klotho has local effects in the kidney where it contributes to kidney function and in relation to this also CKD. Full-length soluble Klotho has been shown to have systemic effects on the vascular system by inducing anti-inflammatory effects and NO-induced vasodilatation. The exact effects of KL1 and KL2 on the vascular system remain to be determined. Furthermore, further research is needed to elucidate the exact systemic effects of full-length soluble Klotho as well as KL1 and KL2 on the heart. Figure is created with BioRender.com.