ADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis?

Abstract

Chronic kidney disease (CKD) is a major health problem, affecting millions of people worldwide, in particular hypertensive and diabetic patients. CKD patients suffer from significantly increased cardiovascular disease (CVD) morbidity and mortality, mainly due to accelerated atherosclerosis development. Indeed, CKD not only affects the kidneys, in which injury and maladaptive repair processes lead to local inflammation and fibrosis, but also causes systemic inflammation and altered mineral bone metabolism leading to vascular dysfunction, calcification, and thus, accelerated atherosclerosis. Although CKD and CVD individually have been extensively studied, relatively little research has studied the link between both diseases. This narrative review focuses on the role of a disintegrin and metalloproteases (ADAM) 10 and ADAM17 in CKD and CVD and will for the first time shed light on their role in CKD-induced CVD. By cleaving cell surface molecules, these enzymes regulate not only cellular sensitivity to their micro-environment (in case of receptor cleavage), but also release soluble ectodomains that can exert agonistic or antagonistic functions, both locally and systemically. Although the cell-specific roles of ADAM10 and ADAM17 in CVD, and to a lesser extent in CKD, have been explored, their impact on CKD-induced CVD is likely, yet remains to be elucidated.

Keywords: a disintegrin and metalloprotease; atherosclerosis; cardiovascular diseases; chronic kidney disease.

Figure 1

ADAM domain structure. A disintegrin and metalloproteinases (ADAM) present on the transmembrane consists of seven domains, namely the prodomain (pro), metalloprotease domain (MP), disintegrin domain (D), cysteine-rich domain (C), EGF-like domain (EGF; except for ADAM10 and ADAM17), transmembrane domain (TD), and cytoplasmic domain (CD). ADAMs are activated after the prodomain (Pro) is cleaved off, after which they can shed, among others, transmembrane proteins, which are released into the circulation. Created with BioRender.com.

Figure 2

Overview of shedding activities of a disintegrin and metalloproteinases (ADAM) 10 and ADAM17 in the kidney. The shedding of ADAM10 and ADAM17 substrates in chronic kidney disease (CKD). (a) Activation of the epidermal growth factor receptor (EGFR) pathway by shedding amphiregulin (AREG) and transforming growth factor α (TGFα) by ADAM17. AREG and TGFα shedding results in the upregulation of ADAM17 on the transmembrane. (b) Additionally, heparin-binding EGF-like growth factor (HB-EGF) is cleaved by ADAM10, also activating the EGFR pathway. (c) Shedding of Klotho is mediated by ADAM10 as well as ADAM17, resulting in soluble Klotho (sKlotho), which exerts renoprotective effects. Membrane-bound Klotho, fibroblast growth factor receptor (FGFR), and fibroblast growth factors 23 (FGF23) are from a trimeric signaling complex regulating kidney homeostasis. (d) ADAM10 and ADAM17 can shed chemokine (C-X3-C motif) ligand 1 (CX₃CL1) and chemokine (C-X-C motif) ligand 16 (CXCL16), producing soluble chemokines. sAREG, sTGFα, sHB-EGF, sKlotho, sCX₃CL1, and sCXCL16 are all released into the circulation and can translocate to the arterial endothelium and affect atherosclerotic processes. Created with BioRender.com.

Figure 3

Simplified overview of mechanisms involved in cardiorenal cross-talk. Upon kidney damage and development of chronic kidney disease (CKD), several primary effects occur that can either directly or via subsequent secondary effects influence atherosclerosis and thus cardiovascular disease (CVD). Although several mechanisms are already known, many more remain to be defined (TBD). Created with BioRender.com.