Adams Family in Kidney Physiology And Pathology Part 1
Mar 17, 2023
ABSTRACT
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1. Introduction
A disintegrin and metalloproteases (ADAMs) family belong to type I transmembrane and secreted metalloendopeptidases proteins, which mediate the cleaving of the extracellular domain (ectodomain) of membrane proteins. The ADAMs regulates several proteins, including growth factors, cytokines, receptors, and adhesion molecules, which play essential roles in numerous biological processes such as cell migration, cell adhesion, proteolysis, and signal transduction. To date, ADAMs have been found in various mammalian genomes, e.g. 37 ADAMs in rats, 34 ADAMs in mice, and 21 ADAMs in humans. ADAMs are fundamental for normal development and morphogenesis, including sperm-egg interaction, embryonic development and differentiation, cell fate determination, and diverse aspects of immunity. Dysregulation of ADAMs is associated with multiple human pathologies such as cardiovascular and neurodegenerative diseases, cancer, asthma, inflflammation, and kidney diseases, and thus provides potential therapeutic targets for these diseases.
ADAMs regulate and coordinate cellular signaling in response to changes in renal physiology and pathology. In this review, we focus on the physiological roles of ADAMs in renal embryological development and summarize the pathological roles of ADAMs in kidney diseases. We also discuss the potential and challenges in targeting ADAMs to prevent and treat kidney diseases.
2. ADAMs structure, regulation, and function
The typical structure of Adams consists of a prodomain, a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor (EGF)-like domain, followed by a transmembrane region, and a cytoplasmic tail (Fig. 1). The cysteine-rich domain and the EGF-like domain are replaced by the membrane-proximal domain in ADAM10 and ADAM17, which are considered atypical family members of ADAMs [1 3]. Structurally, the prodomain is followed by the metalloprotease domain, and their interaction is essential for Adams's proteolytic activity [2, 4]. To some degree, the disintegrin domain can selectively bind to integrins to mediate cell adhesion, cell migration, and cell-cell interactions. The cysteine-rich domain contains a hyper-variable region (HVR), that contributes to Adams's function by recognizing their substrates and regulating the catalytic activity. This region may be involved in modulating subcellular localization and protein-protein interactions [5]. The different composition of the cytoplasmic tails is crucial for their varying functions in metalloprotease activity, intracellular signaling, and subcellular localization.
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The extracellular and intracellular pathways of ADAM activation are intricate, as regulation often occurs through conformational changes, activators, or inhibitors. After biosynthesis in the endoplasmic reticulum and maturation in the Golgi compartment, ADAMs secrete inactive zymogens. The cytoplasmic tail controls the retention of properly folded ADAMs in the Golgi compartment by an unidentified mechanism, which impedes the release of ADAMs activity at the cell membrane [6, 7]. The prodomain inhibits Adams activity via maintaining the metalloproteinase domain in an inactive conformation, and the prodomain cleavage by furin-type proteases and PC7 release the catalytical activity in a process occurring when transiting to the cell surface [1,4,8]. In addition to the effects of conformational changes on ADAMs activities, ADAMs activities also suppress by endogenous tissue inhibitors of metalloproteinases (TIMPs), which have a specific inhibitory effect on various ADAMs family members.
ADAM-mediated cleavage of ectodomain shedding is a process of releasing the extracellular domain by proteolytic cleavage. The diverse substrates of ADAMs include growth factors, cytokines, chemokines, adhesion molecules, proteins of the extracellular matrix, and receptors and ligands of signaling pathways, and thus functions of ADAMs ectodomain shedding play a prominent role not only in cell proliferation, differentiation, and adhesion but also in signal transduction. Moreover, ADAM-mediated ectodomain shedding has been identified in exosomes, potentially contributing to intercellular communication [9,11]. In addition to their roles in ectodomain shedding, ADAMs also have the ability to modulate intracellular signal transduction. The ADAMs play a major role in transmembrane protein shedding, an initiating step for regulated intramembrane proteolysis (RIP) that releases intracellular domains and regulates intracellular signaling events. Notch signaling and amyloid-precursor protein processing are typical examples of RIP.
In the past few years, ADAM10 and ADAM17 were the most studied family members. Several researchers have confirmed the roles of ADAM10 and ADAM17 in the renal physiological and pathological processes (Table 1). ADAM10 is expressed in renal tubular cells and is involved in several kidney diseases [12]. While ADAM17 is weakly expressed in proximal tubules, glomerular endothelium, and mesangium, its expression is markedly induced in interstitial fibrosis and tubular atrophy [13, 14]. The importance of ADAM-mediated signaling in the kidney has been recognized and highlighted. Next, we review recent insights into the molecular cell biology of ADAMs in the context of normal and abnormal kidneys and discuss the precise functions of ADAM proteins in nephrogenesis, kidney cellular effects, and kidney diseases separately.
3. ADAMs in nephrogenesis
ADAMs are essential proteases involved in embryo development via controlling cell proliferation, cell differentiation, cell migration, and organ morphogenesis. Diverse phenotypes have been observed in ADAM knockout mice due to the broad expression of ADAMs in mammalian tissues, but only ADAM10, ADAM17, and ADAM19 null mice have defects in embryo development [15]. In this review, we focus on extensive information on the ADAM family during kidney development, and briefly summarize the roles of the two well-studied members, ADAM10 and ADAM17.
ADAM10 is best known for its function in ligand-dependent Notch S2 cleavage, which is responsible for mediating the Notch pathway. Notch signaling has multiple effects throughout the development of diverse tissues and cell types. In kidney development, Notch signaling controls proximal tubular epithelial cell fate as well as collecting duct cell composition. High expression of Notch2 is observed in the developing ureteral bud (UB) and ADAM10 is also highly expressed in the late UB, indicating that ADAM10 is involved in metanephric development [16]. Moreover, slit genes are expressed in the metanephric mesenchyme, while Robo1 is also found in the UB. Thus, ADAM10 may participate in regulating Slit-Robo signaling during nephrogenesis [17, 18]. It showed that ADAM10 deficiency in UB reduced principal cells/intercalated cell ratios in the collecting duct with a reduction of Notch activity. ADAM10 deficiency mice present with polyuria and hydronephrosis, suggesting that these mice have defects in urinary concentration. Taken together, ADAM10 plays an indispensable role in determining the cell fate of collecting ducts, which is partially necessary for the normal development of renal collecting ducts [19]. During development, glomerular endothelial cells interact with mesangial cells and podocytes to generate the mature glomerular vascular structure. Normal Notch signaling is crucial for podocyte and mesangial cell maturation, which is essential for proper glomerular development [20, 21]. Notch1 deficiency, as well as inactivation of ADAM10 in endothelial cells, results in similar glomerular defects that are rescued by overexpression of Notch signaling in ADAM10 deficiency mice. These findings indicate that ADAM10- dependent Notch signaling plays a central role in developing glomerulus [22]. Furthermore, Farber’s group reported that ADAM10/Notch signaling promoted the maturation of the glomerular vasculature [23]. In addition, increased expression of ADAM10 has been detected in differentiated podocytes [24]. Therefore, ADAM10 contributes to diverse aspects of renal development (Fig. 2).
Fig. 2. Roles of ADAM10 signaling in kidney development. The Notch receptor is activated by ligand binding after ADAM10 mediated the S2 site cleavage of Notch ligands and second gamma-secretase proteolytic cleavage at the S3 site. During nephrogenesis, ADAM10/Notch signaling is partially necessary for the normal development of renal collecting ducts. And normal Notch signaling is crucial for podocyte and mesangial cell maturation, which is essential for proper glomerular development. In addition, ADAM10/Notch signaling promotes the maturation of the glomerular vasculature.
ADAM17 participates in cell proliferation, differentiation, and migration as a pleiotropic regulator of organ development, and these effects are mainly associated with EGFR signaling. ADAM17-deficient mice and EGFR-signaling defective mice show similar developmental defects, which may be explained by decreased levels of EGFR ligands and inadequate EGFR activation [25]. The EGFR pathway also plays a crucial role in kidney development by contributing to the induction of metanephric structures. Several EGF family members, such as EGF, TGFa, and HB-EGF, are expressed during metanephric development and may contribute to nephron development through EGFR activation. In vitro studies demonstrated that EGFR ligands EGF and TGFa stimulated embryonic kidney cell growth and proliferation [26]. The deletion of EGFR ligands EREG, AREG, and TGFa impairs the process of UB morphogenesis in vitro cultures of rat metanephros [27]. In human nephrogenesis, immunoreactivity to HB-EGF can be detected in the UB from the E14.5 day and persisted throughout embryogenesis, whereas immunoreactive EGF and TGFa are detected in all metanephric structures from the 7th week and decrease during the process of nephrons differentiation [28, 29]. Thus, the role of ADAM17-mediated EGFR signaling during kidney development deserves further investigation. Interestingly, ADAM17 also participates in generating the active form of Notch, which is important in glomerular development [30]. Conditional knockout mice in the kidney could further elucidate the contribution of ADAM17 during nephrogenesis.
4. Cellular effects of ADAMs in the kidney
The roles of ADAM17 in the regulation of tubular epithelial cells, mesangial cells, and podocytes are summarized in Fig. 3, and we also briefly discuss the cellular effects of ADAM10.
4.1. Tubular epithelial cells
Upon kidney injury, ADAM17 is upregulated and activated in TECs, inducing inflflammation and proliferation. ADAM17 releases EGFR ligands TGFa and HB-EGF to activate EFGR signaling, resulting in pro-inflammatory factors upregulation and inflammatory cell infiltration. A study in cultured TECs showed aldosterone-induced protein-inflammatory gene upregulation and pro-inflammatory factors overexpression via ADAM17/EGFR activation. Blockade of the ADAM17/EGFR pathway in these cells had anti-inflammatory effects in response to aldosterone [31]. Ford et al reported that the increased oxidative stress in high glucose-promoted TEC injury was prevented by ADAM17 inhibition, suggesting that ADAM17 is an important mediator of renal tubular inflflammation [32]. These findings highlight ADAM17 as an important effector of inflflammation upon TEC's injury. Moreover, activation of the ADAM17 pathway induces TEC's proliferation and epithelial-to-mesenchymal transition (EMT), which is characterized by increased expression of fibronectin and cellular collagen [33,35]. The ADAM17-mediated sustained activation of EGFR signaling interacts with profibrotic factors release and induces interstitial fibrosis. These findings point to a complex regulatory network between ADAM17 and TECs in inflflammation and fibrosis.
4.2. Mesangial cells
Renal mesangial cells, the major constituents of the glomerular mesangium, are critically involved in various glomerular injuries. In response to injury, mesangial cells proliferated and were activated to produce mesangial matrix components, such as collagen Ⅳ, fibronectin, and laminin, which contribute to excess extracellular matrix (ECM). Moreover, the activation of mesangial cells also induces the secretion of various inflammatory cytokines, chemokines, and adhesion molecules, promoting the accumulation of inflammatory cells and the process of renal fibrosis.
ADAM17 is activated in response to injury, leading to mesangial cell proliferation and ECM accumulation. As mentioned above, ADAM17 participates in the shedding of EGFR ligands to activate EGFR and induces downstream ERK phosphorylation. The initiation of downstream signaling drives cell proliferation, migration, and apoptosis [36, 37]. Moreover, by engaging the EGFR pathway, ADAM17 induces glomerular matrix accumulation leading to glomerulosclerosis and interstitial fibrosis. Studies in mesangial cells have shown that in high glucose conditions, ADAM17 is activated and regulates profibrotic TGFa in the accumulation of matrix proteins [38, 39]. These effects are abrogated by TAPI2, an ADAM17 inhibitor, via blocking glomerular collagen accumulation [40]. Additionally, ADAM10 and ADAM17 mediate the release of CXCL16 in mesangial cells, promoting cell proliferation and migration. Notably, both ADAM10 and ADAM17 appear to participate in the recruitment of immune cells into the glomerulus to drive the inflammatory process [41]. In addition, ADAM15 participates in the reorganization of the mesangial matrix and the migration of mesangial cells in diseases [42]. These findings indicate that ADAMs are centrally involved in the response of mesangial cells following injury.
4.3. Podocytes
Podocytes play vital roles in maintaining the glomerular filtration barrier and thus are the major target of injury in various glomerular diseases. Under injury, podocytes undergo morphological changes, including foot process effacement, irregular shape, and cytoplasmic droplets, which alter the construction of the glomerular basement membrane leading to proteinuria. Furthermore, podocytes generate reactive oxygen species and increase the expression of TGFb and chemokine receptors to activate inflammation-associated signals, which in turn promotes podocyte injury [43].
The increased expressions of ADAM10 and ADAM17 constitute the main driver of podocyte injury in glomerular diseases. Sustained podocyte injury leads to ADAM17/EGFR signal activation, which decreases podocyte permeability and induces podocyte regeneration. Dey et al showed that ADAM17-dependent EGFR activation changed podocyte permeability via promoting protein zonula occludens-1 rearrangement, whereas these effects were attenuated by EGFR inhibition and ADAM17 down-regulation [44]. In cultured human podocytes, inhibition of ADAM17 reduces constitutive and phorbol ester-induced shedding of the EGFR ligand TGFa as well as cellular proliferation [13]. Moreover, ADAM10 and ADAM17 are involved in the release of CXCL16 from podocytes, which plays an important role in mediating inflammatory factors and podocyte migration. CXCL16 is a scavenger receptor, and its release mediates the uptake of ox-LDL to induce reactive oxygen species and fibronectin in podocytes [45]. Another study revealed that ADAM10-mediated CXCL16 release modulated the actin cytoskeleton, as well as promoted podocyte migration [46]. Notably, ADAM10 has been identified as the major regulator for Notch signaling, which takes part in the development of glomerular disease. Several studies have suggested that Notch activation in podocytes contributed to foot process effacement and subsequently albuminuria and glomerulosclerosis [47]. The complex regulatory network between ADAM10 and Notch signaling in podocyte injury still needs to be elucidated.
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