Adams Family in Kidney Physiology And Pathology Part 2

5. ADAMs in kidney diseases 

ADAMs signaling is fundamental for modulating cellular processes during kidney development, whereas upregulation and activation of ADAMs are involved in kidney diseases. In this review, we focus on the prominent roles of ADAM10 and ADAM17 with ubiquitous expression in kidney diseases. Notably, ADAM17/EGFR signaling is not only involved in the initiation of AKI and its progression to CKD but also is of importance in other kidney diseases as shown in Fig. 4.

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5.1. Acute kidney injury

AKI is characterized by a rapid increase of serum creatinine, manifests with oliguria or anuria, and presents renal functional and structural changes. Several studies have confirmed that activation of ADAM17 contributes to the development of AKI, suggesting that ADAM17-mediated shedding disrupts cellular homeostasis and promotes tissue injury [33, 48, 49]. In the progression of AKI, ADAM17 overexpression drives tubular epithelial cell injury, mainly by activation of EGFR signaling to induce inflflammation and proliferation. The sustained activation of ADAM17/EGFR signaling after AKI upregulates the synthesis and release of pro-inflammatory and pro-fibrotic factors leading to macrophage infiltration as well as renal fibrosis [35, 50]. Moreover, ADAM17 induces IL-6 trans-signaling by shedding the membrane-bound IL-6 receptor [51], which has been shown to drive crescentic glomerulonephritis [52, 53] and lupus nephritis [54]. On the other hand, ADAM17 induces the shedding of KIM-1. The shedding of constitutive and induced KIM-1 by ADAM17 reduces the apoptotic capacity of TECs and restricts the recovery of the kidney [55]. Additionally, ADAM10 may be important in renal tubule injury. Activated ADAM10 mainly expresses in TECs in experimental models of AKI. ADAM10 is involved in the release and redistribution of Meprin A, which is responsible for inflflammation and ECM remodeling in AKI [56]. ADAM10 also takes part in KIM-1 ectodomain release, and ADAM10-induced KIM-1 shedding is essential for the modulation of phagocytic clearance of apoptotic cells after AKI [57]. Collectively, ADAM17 and ADAM10 are overexpressed and activated in renal tubular cells and play a damaging role in AKI.

5.2. Chronic kidney disease

ADAMs not only participate in the initiation of AKI but also are critical for the progression of CKD. Higher ADAM17 expression has been observed in the kidneys of CKD patients, co-localizing with TGFa in fibrotic regions, highlighting the importance of the pro-inflammatory and profibrotic roles of ADAM17 in the progression of CKD [13]. Moreover, circulating ADAM17 activity is markedly increased with CKD progression, and it has been identified as an independent risk factor for renal outcomes [58]. In the unilateral ureteral obstruction (UUO) animal model, the activation of ADAM17 is relevant to the kidney fibrotic response to various tubular injuries [33, 34]. In addition, the upregulation of ADAM10 has been observed in both CKD patients and UUO mice, which aggravates kidney damage resulting in increased fibrotic factors and EMT of tubular epithelia [59]. Moreover, Li et al have shown that ADAM10 expression increased during the progression of IgA nephropathy and that the continuous activation of ADAM10, in turn, promoted kidney interstitial fibrosis and renal dysfunction [60]. Importantly, our recent research found that ADAM19 is upregulated in the acute-chronic kidney model, along with increased expression of ADAM19 in the kidney of IgA nephrology patients with severe classes [61]. Upregulation of ADAM19 directly induced fibrotic genes, CCL2, and macrophage infiltration, while depletion of macrophages could ameliorate the fibrotic effects of ADAM19 [61]. Moreover, upregulation of ADAM19 induced accumulation of the Notch1 intracellular domain, whereas the Notch1 pathway antagonist could reduce CCL2 level and macrophage infiltration [61]. These findings provide new insights into the expression of ADAM19 during kidney diseases and offer potential mechanisms of ADAM19 underlying renal fibrosis.

Secondary hyperparathyroidism (SHPT) is a common complication in CKD patients, characterized by mineral and skeletal abnormalities, and predisposition to vascular stiffness and calcification. Parathyroid hyperplasia is in part ascribed to EGFR activation, and inhibition of EGFR activation should effectively attenuate the progression of SHPT. Notably, in patients with SHPT, ADAM17 levels are elevated in the parathyroid tissues, exacerbating EGFR-driven nodular hyperplasia. Arcidiacono et al have found that suppression of ADAM17 expression attenuated parathyroid gland enlargement and decreased parathyroid hormone levels in SHPT rats [62]. Importantly, 1,25-dihydroxy vitamin D inhibition of ADAM17 not only ameliorates the progression of SHPT but also attenuates ADAM17/TGFa-driven systemic inflflammation [63].

CKD represents a well-established risk factor for cardiovascular (CV) events. The rate of CV events is high with kidney disease progression, and the broad spectrum of CV events in this population is crucial for CKD prognoses. ADAMs are involved in CV disease development and progression, for example, ADAM17 is associated with an increased risk of CV death in patients with coronary artery diseases [64]. It deserves more attention to the role of ADAMs in the progression of renal function and CV events in CKD patients. Circulating ADAM activity from 2570 CKD patients has been assessed in the NEFRONA study, which indicates that ADAM activity is independently associated with CV events in CKD patients [58]. Moreover, the high level of ADAM17 is correlated with a high level of fibroblast growth factor 23, which is an important indicator of oxidative stress and CV risk in CKD patients [65]. Hence, the possible pathogenic link between these conditions is represented by the enhanced production of ADAM17-released TGFb, which acts as a mediator in the cross-talk kidney and CV disease. Similarities have also been found among the matrix metalloproteinases family as discussed in recent reviews [66, 67]. All of these important pieces of evidence have confirmed that metalloproteinases contribute to reinforcing the risk-oriented from CKD to CV diseases.

5.3. Diabetic kidney disease

Diabetic kidney disease (DKD) is characterized by persistent albuminuria and progressive decline in kidney function, accompanied by the accumulation of ECM and fibrosis. Growing evidence has shown that ADAM10, ADAM17, and ADAM19 are induced explicitly in both glomeruli and tubules in DKD patients [68, 69]. Alan et al found that the overexpression of serum ADAM10 was remarkably associated with advanced glycation end products, which have been recognized as important contributors to diabetic complications [70]. Moreover, upregulation of urinary ADAM17 is observed in diabetic patients with albuminuria and is accompanied by elevated urinary angiotensin-converting enzyme 2 (ACE2), which may indicate a potential role of ADAM17-mediated ACE2 in DKD pathogenesis [71].

In line with these, hyperglycemia in type 1 diabetic mice upregulates renal ADAM17 expression and induces ADAM17 activation, which enhances oxidative stress and extracellular matrix accumulation. Of note, mice treated with TMI-005, an ADAM17 inhibitor, are protected against renal damage by decreasing type Ⅳ collagen, Nox4, and NADPH oxidase activity [32]. More importantly, ADAM17 knock-out mice have been used in protecting renal pro-inflammatory and pro-fibrotic injury caused by type 1 diabetes mellitus, which shows that specific endothelial ADAM17 deletion prevents renal fibrosis and inflflammation, and specific proximal tubular ADAM17 deletion protects from pro-fibrotic events, podocyte loss, and attenuates the renal RAS [72]. In db/db mice, ADAM17 is upregulated and co-localized with ACE2 in renal tubules. One study reported that activated ADAM17 impaired kidney function by inducing ACE2 activity, and treatment with rosiglitazone ameliorated the hyperglycemia and restored the ADAM17, thereby attenuating AGE-induced kidney injury in db/db mice [73]. Another study reported that in db/db mice, exercise training alone or combined with metformin protected against albuminuria by preventing ADAM17-mediated renal ACE2 shedding [74]. ADAM17 is significantly increased in kidneys of streptozotocin (STZ)-induced diabetic rats, while ADAM17 inhibition could ameliorate renal inflflammation [75]. Furthermore, Src-dependent EGFR transactivation in STZ-induced diabetic nephropathy leads to podocyte depletion and ECM accumulation, whereas ADAM17 inhibition abrogates EGFR phosphorylation, underscoring the interaction between ADAM17 and EGFR signaling in DKD [40]. The deficiency of TIMP3, an endogenous ADAM17 inhibitor, aggravated membrane thickness and mesangial expansion in diabetic mice, contributing to oxidative stress and autophagy through FoxO1/STAT1 interplay [76]. Besides, podocyte deletion of ADAM17 attenuates STZ-induced ECM accumulation, glomerular damage, and urinary albumin, which indicates that targeting ADAM17 signaling may be therapeutic for DKD.

5.4. Polycystic kidney disease

Polycystic kidney disease (PKD) is characterized by gradually growing renal cysts, resulting in progressive fibrocystic renal disease and renal dysfunction. As PKD progresses, changes in cell proliferation, apoptosis, and adhesion, as well as increased ECM and cellular metabolism play critical roles in the aggravation of kidney injury. ADAM17/EGFR signaling may also be important in the development of PKD. Excessive expression and activation of ADAM17 have been identified in PKD cells, while ADAM17-regulated EFGR shedding induces EGFR/MAPK/ERK pathway activation and probably promotes TEC's proliferation. Moreover, changes in cellular metabolism and glucose consumption are accompanied by renal cyst formation and expansion, and ADAM17 inhibition participates in blocking these effects [78]. In addition, PKD1 mutation alters cell polarity and adhesion via intensifying E-cadherin shedding, which is modulated by increased ADAM10. Specific inhibition of ADAM10 serves as a strategy to ameliorate cystogenesis [79]. Presently, some important advances in the treatment of PKD have focused on halting the progression of kidney cysts and attenuating the decline of kidney function, whereas no newer studies regarding podocytes have been published. Although, ADAMs represent promising therapeutic targets to attenuate kidney cyst progression, the future management of PKD will probably involve multidrug therapy to target distinct molecular pathways that influence cyst fluid secretion, cell proliferation, inflflammation, and fibrosis.

5.5. Kidney transplant dysfunction

Dysregulated ADAMs have also been recognized in allograft nephropathy, which as important contributors to inflammation, immune response, and fibrosis. A study observed that massive ADAM10 expression was together with infiltrating T cells in kidney transplant patients with acute interstitial rejection, suggesting that ADAM10 may regulate immune response and inflammation during acute allograft rejection [12]. ADAM17 signaling involved in the induction of inflammation during allograft nephropathy has also been assessed. ADAM17 is expressed and activated in TECs of transplanted kidneys, and the activation of ADAM17 promotes the shedding of tumor necrosis factor receptors [80]. Other studies further demonstrated that ADAM17 expression was upregulated in chronic renal allograft rejection, which may be responsible for modulating inflammation and fibrosis [14, 81]. In addition, enhanced ADAM19 expression was detected in glomerular sclerotic lesions, renal tubule, and inflammatory CD4+ cells in chronic allograft nephropathy, as well as in patients with the acute rejection of kidney allografts [82].

6. Therapeutic outlook

ADAM family is emerging as a novel therapeutic target in patients with kidney diseases and associated complications. Importantly, the roles of ADAMs in human kidney disease will be validated after specific therapies targeting its pathways. To date, small molecule inhibitors modulating metalloproteinases focus mainly on downregulating the proteolytic activity of ADAMs and matrix metalloproteinases. The first generation of small molecule inhibitors targets the zinc ion of metalloproteinases, which shows poor selectivity and several side effects [83]. Thus, specifically targeted small molecules are under development and clinical trials, such as GI254023X with high selectivity for ADAM10 [84]. On the other hand, protein therapeutics, based on antigen-antibody and TIMP-ADAMs interaction, offer the superior potential for selectivity and stability. Although TIMPs control the activity of ADAMs in space and time precisely, ADAMs-independent interactions of TIMPs make them controversial protein scaffolds for treating diseases. Therefore, understanding the ADAMs-independent function of TIMPs is critical to developing the next generation of TIMP scaffolds as efficient therapeutics. Moreover, natural antibodies, targeting the surface of the catalytic domain, are emerging with low immunogenicity and toxicity. Besides, further understanding of the particular substrates of ADAMs in kidney diseases could aid the development of highly targeted treatments. Since the molecular characterization of ADAMs and regulators vary in different tissues, understanding Adams's homeostasis throughout the body is required to harness its full potential for therapeutic modulation.

7. Outstanding questions

ADAMs are important regulators in kidney embryogenesis and pathological progression. In kidney embryo development, ADAMs participate in cell proliferation, differentiation, and migration, mainly via ADAM10-mediated Notch signaling and ADAM17-mediated EGFR signaling. Upon kidney injury, ADAMs are re-expressed and activated in proximal tubules, glomerular mesangium, and podocytes, which contributes to inflflammation and fibrosis. The field continues to advance, both with the recognition of ADAMs substrate in kidney diseases and a growing understanding of the mechanisms that underpin the associations between the ADAM family and kidney diseases. Although the damaging effects of ADAMs in kidney injury have been established, the cellular effects of ADAMs are highly diverse in different kidney diseases, and the precise signaling due to ADAMs activation remains largely elusive. Therefore, there are still several important questions needed to be further addressed. On the one hand, the foremost question will be which substrates of ADAMs determine certain kidney pathological processes, and whether aspects of kidney injury induced by ADAMs are due to particular effectors remains unknown. On the other hand, understanding how ADAMs activity is regulated in different cells in an environment-dependent manner is crucial for unraveling insights into its roles in kidney pathology. Importantly, clinical translation of experimental data to the human system remains challenging. The targets of ADAMs might regulate cellular processes beyond the kidney and their pharmacological targeting might result in unexpected side effects. Hence, considering the tissue specificity and degree of ADAMs modulation will be essential to maximize its protective effect. Despite the obvious difficulties, based on the ubiquity and importance of ADAMs in physiology and pathology, knowledge gained from the kidney may advance our understanding of potential applications of the Adams family and provide novel translational insights into other organs.

8. Search strategy and selection criteria

Data for this Review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms “kidney”, “ADAM”, and “nephrogenesis”. Abstracts and reports from meetings were included only when they related directly to previously published work. Only articles published in English between 1980 and 2021 were included.

Contributors

Declaration of Competing Interest

The authors have declared that no competing interest exists.

Acknowledgments

This study was supported by funds from the National Natural Science Foundation of China (81770674) and the Primary Research and Development Plan of Zhejiang Province (2020C03034) to Fei Han. The funding organization did not have a role in the design, interpretation, or writing of this review article.

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