A Disintegrin And Metalloprotease 17 Research Articles (Page 1)

A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound enzyme that cleaves cell-surface proteins. Here, we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub, located in the paraventricular nucleus of the hypothalamus (PVN), upon stimulation by angiotensin II (Ang-II). For Ang-II-induced disinhibition, targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons. Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17. Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II's pressor response. Using conditional and targeted knockout models of ADAM17, an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension. Collectively, this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.

ADAM17/ACE2 interaction mediates cadmium-induced brain damage and neuroinflammation in Wistar rats.

BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen that affects swine and causes substantial economic losses in the global pig industry. Despite the availability of vaccines, it remains crucial to explore innovative therapeutic strategies to control PRRSV infections. Magnolol, a bioactive compound extracted from the root and bark of Magnolia officinalis, has demonstrated broad-spectrum antiviral activity in previous studies.MethodsThe cytotoxicity of magnolol was determined by the CCK-8 method. RT-qPCR, western blot, and immunofluorescence were used to study the inhibitory effect of magnolol on PRRSV N gene and protein expression through antiviral assay and viral attachment, internalization, replication and release assays. The effect of magnolol on immune-related gene expression was analysed by RT-qPCR.ResultsWe found magnolol hinders multiple facets of the PRRSV lifecycle, encompassing the stages of viral attachment and replication. Furthermore, magnolol enhances the expression of pivotal cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-α (TNF-α), during PRRSV infection, thereby reinforcing the host cells' capacity to mount an effective antiviral defence. Additionally, it exerts inhibitory effects on PRRSV replication by upregulating the expression of a disintegrin and metalloprotease 17 (ADAM17) at both the protein and mRNA levels.ConclusionsIn this study, we provide evidence demonstrating the potent efficacy of magnolol in inhibiting PRRSV replication within Marc-145 cells. Our findings underscore the potential of magnolol as a novel antiviral agent for the PRRSV control.

Hyaluronan is a primary component of the endothelial glycocalyx and participates in mechanotransduction of shear stress which results in vasodilation. However, extracellular hyaluronan interacts indirectly with endothelial cells via its cell surface receptor CD44, which has recently been demonstrated to be mechanosensitive. CD44 is also a substrate for A Disintegrin And Metalloprotease-17 (ADAM17) , a sheddase that is elevated in the vasculature of individuals with type 2 diabetes (T2D). Of note, T2D is characterized by reduced flow-mediated dilation (FMD), indicative of impaired shear stress mechanotransduction. Thus, we hypothesized that increased endothelial ADAM17 activity causes cleavage of CD44 leading to impaired shear stress mechanotransduction. In support of this hypothesis, we demonstrate that ADAM17 overexpression in endothelial cells sheds CD44 from the cell surface and reduces the cellular responses to flow-induced shear stress (15 dynes/cm 2 ; 24hrs). We also demonstrate the specificity of ADAM17 for CD44 using a cell-free assay in which co-incubation of recombinant human active ADAM17 (rh-ADAM17; 5ug) with recombinant human CD44 (rh-CD44; 500ng), for 8 hours, results in the generation of cleaved fragments of CD44. This cleavage is prevented with co-incubation of TAPI-0 (50uM; 8hrs), an ADAM17 inhibitor. Furthermore, pharmacological activation of ADAM17, via a phorbol 12-myristate 13-acetate (PMA; 1uM, 2hrs/24hrs), cleaves CD44 and impairs mechanotransduction of shear stress in endothelial cells. Notably, these effects of PMA are prevented by TAPI-0 (50uM; 2hrs/24hrs). To further establish the consequences of ADAM17-mediated cleavage of CD44, and likely other mechanosensors, we corroborate that endothelial exposure to rh-ADAM17 (1ug/mL, 1hr) reduces FMD in isolated mouse mesenteric arteries, without effecting endothelium-independent vasodilation. Taken together, these data suggest that ADAM17-mediated cleavage of CD44 may represent a novel mechanism contributing to endothelial dysfunction in T2D. Funding: R01HL151384, R01HL153264, and AHA23PRE1020897. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Lung cancer is the most lethal and common cancer worldwide, which comprises two main subtypes, non-small cell lung cancer and small cell lung cancer (SCLC), accounting for ∼85% and ∼15%, respectively, of all diagnoses. SCLC is a highly aggressive neuroendocrine malignancy which is detected in two thirds of SCLC patients at a late stage with a dismal 5-year survival rate of less than 5%. This poor outcome is largely due to the stagnated clinical management of SCLC over the last 3 decades, comprising first-line platinum-based chemotherapy with etoposide, which, despite initial high response rates, is associated with rapid disease relapse due to acquired chemoresistance. Therefore, there is a pressing clinical need to identity new molecular drivers of SCLC which can serve as therapeutic targets. In this regard, A Disintegrin And Metalloprotease 17 (ADAM17) is the major “sheddase” for >80 membrane-tethered pro-tumourigenic substrates, including epidermal growth factor receptor ligands, notch receptor and tumour necrosis factor-α, which control many cellular processes (e.g. inflammation, proliferation) in immune and non-immune cells. Therefore, ADAM17 modulates key physiological and pathophysiological cellular processes. Despite the large body of data implicating ADAM17 in lung cancer, the pathological role of ADAM17 in SCLC is unknown. Using our unique highly relevant and well-established clinical and preclinical models, including SCLC patient biopsies, the Rb1fl/fl;Trp53fl/fl (RP) and Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) genetic mouse models, patient-derived xenografts and human SCLC cell lines, as well as proteomics pipeline and a suite of biochemical and molecular biology techniques, we aim to define the role of ADAM17 in SCLC. ADAM17 expression, interactome and substrate repertoire was investigated while the anticancer activity of ADAM17 inhibitors in SCLC was assessed. This research therefore could pave the way for the development of novel therapeutic and biomarker avenues for SCLC. Citation Format: Mohamed I. Saad, Karen Hon, Jelena Solujic, Teresa Weng, Arash Badiei, Clifford Young, Stefan Düsterhöft, Daniel Gough, Stefan Rose-John, Peter Hoffmann, Phan Nguyen, Brendan Jenkins. Investigating the novel role of the protease A Disintegrin And Metalloprotease (ADAM)-17 in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5114.

Spinal ADAM17 contributes to the pathogenesis of painful diabetic neuropathy in leptin receptor-deficient mice.

Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists.

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role in the cellular response to hypoxia, which plays a crucial role in the induction of abnormal angiogenesis and metastasis. Understanding the mechanism for the regulation of angiogenesis by HIF-1α-regulating miRNA will contribute to developing the strategy to prevent metastasis. We conducted a functional screening for HIF-1α-inhibiting miRNAs by evaluating the effects of miRNA mimics on HIF-1α expression and identified miR-5586-5p as an angiogenesis inhibitor through a mechanistic study. Angiogenic activity was assessed by tube formation assays using HUVEC cells exposed to conditioned media from miRNA-transfected breast cancer cells. In vivo activity of miR-5586-5p was examined through intratumoral injection of miRNA in orthotopic xenograft mice established by injecting MDA-MB-231 cells into the mammary fat pads of BALB/c nu/nu mice. The expression of the critical proangiogenic factors vascular endothelial growth factor A (VEGFA) and angiopoietin-like protein 4 (ANGPTL4) was inhibited by miR-5586-5p. Migration and tube formation of human umbilical vein endothelial cells were reduced in the conditioned medium prepared from miR-5586-5p-transfected cells. miR-5586-5p also suppressed the expression of heparin-binding EGF-like growth factor (HBEGF) and a disintegrin and metalloprotease 17 (ADAM17), which play a role in hypoxic signaling to induce the expression of VEGFA and ANGPTL4. HIF-1α, HBEGF, and ADAM17 were verified as the direct targets of miR-5586-5p responsible for the angiogenesis-suppressing function of miR-5586-5p. Expression levels of miR-5586-5p were lower in tumor tissues than in neighboring normal tissues of breast cancer patients. The expression of miR-5586-5p was inversely correlated to those of HIF-1α, HBEGF, ADAM17, VEGFA, and ANGPTL4. Angiogenesis and subsequent tumor growth were suppressed by intratumoral injection of miR-5586-5p in orthotopic MDA-MB-231 xenografts in mice. A potent tumor-suppressive function of miR-5586-5p applicable for the development of a novel cancer treatment strategy is herein described.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA. Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism. The TREM2 levels were decreased in BV2 cells exposed to IH for 24hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions. TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.

Fibrosis leads to structural damage and functional decline and is characterized by an accumulation of fibrous connective tissue and a reduction in parenchymal cells. Because of its extremely poor prognosis, organ fibrosis poses a significant economic burden. In order to prevent and treat fibrosis more effectively, potential mechanisms need to be investigated. A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound protein. It regulates intracellular signaling and membrane protein degradation. Fibrosis mediated by ADAM17 has been identified as an important contributor, although the specific relationship between its multiple regulatory functions and the pathogenesis is unclear. This article describes ADAM17 activation, function, and regulation, as well as the role of ADAM17 mediated fibrosis injury in kidney, liver, heart, lung, skin, endometrium, and retina. To develop new therapeutic approaches based on ADAM17 related signal pathways.

Microglia, the resident immune cell in the brain, contributes to neuroinflammation and neurogenic hypertension by secreting various cytokines and chemokines. ADAM17 shedding of these signaling molecules) in microglia modulates synaptic function but the consequences of this process have not been studied in neurogenic hypertension. Accordingly, we hypothesize that deletion of ADAM17 in microglia opposes microglia activation and cytokine secretion thus preventing the development of neuroinflammation in salt-sensitive hypertension. To test our hypothesis, a new mouse model (ADAM17::CX3CR1-CreERT2; A17-Mic-/-) amenable for selective deletion of ADAM17 in microglia was developed. Following the initiation of deoxycorticosterone acetate plus salt (DOCA-salt) hypertension, tamoxifen was injected intracerebroventricularly to delete ADAM17 in microglia and blood pressure (BP) monitored over 3 weeks. In A17-Mic-/- mice, lacking ADAM17 in microglia, the BP increase induced by DOCA-salt treatment was blunted compared to control mice (127.4±5 vs. 143.4±4 mmHg, P<0.05). However, it was not abated in iRhom2-/- mice (149.5±3 mmHg), lacking the rhomboid protein involved in ADAM17 maturation in microglia, suggesting possible compensation by iRhom1. Interestingly, A17-Mic-/- mice showed a reduced level of proinflammatory cytokines and chemokines in the plasma, including TNF-α (A17-Mic-/-: 5.21±0.97, iRhom2-/-: 3.867±1 vs. control: 20.72±4 pg/mL), IL-6 (A17-Mic-/-: 36.53±11.33, iRhom2-/-: 91.41±14 vs. control: 79.65±15.72 pg/mL) and G-CSF (A17-Mic-/-: 508.4±98.7, iRhom2-/-: 3523±897 vs. 838.2±238.2 pg/mL) and MCP-1 (A17-Mic-/-: 38.41±9, iRhom2-/-: 51.87±7 vs. control: 75.52±12 pg/mL), respectively (P<0.05). Together, our data suggests that conditional deletion of ADAM17 opposes the activation of microglia and reduces pro-inflammatory cytokine and chemokine expression in hypertension. Overall, our data highlights the pivotal role of microglial ADAM17 in regulating salt-sensitive hypertension and the associated inflammation.

BACKGROUNDColorectal cancer (CRC) is one of the most frequently encountered malignant tumors in clinical settings. Proteins encoded by the testis-expressed gene 14 (TEX14) are imperative for spermatogenesis, necessitating intercellular bridges between germ cells. Anomalous expression of TEX14 has also been associated with the proliferation and differentiation of certain tumor cells. Recombinant A disintegrin and metalloprotease 17 (ADAM17) is known as a membrane-bound protease that regulates cellular activities and signal transduction by hydrolyzing various substrate proteins on the cell membrane. We hypothesize that TEX14 and ADAM17 may serve as potential biomarkers influencing the staging, invasion, and metastasis of CRC.AIMTo probe the correlation between TEX17 and ADAM17 profiles in the CRC tissues of elderly patients and their association with CRC staging, invasion, and metastasis.METHODSWe gathered data from 86 elderly patients diagnosed pathologically with CRC between April 2020 and December 2023. For each patient, one sample of cancer tissue and one sample of adjacent normal tissue were harvested. Real-time fluorescence quantitative PCR measured the mRNA profiles of TEX14 and ADAM17. Immunohistochemistry ascertained the positivity rates of TEX14 and ADAM17 expressions. Clinical pathological features of neoplasm staging, invasion, and metastasis were collected, and the association between TEX14 and ADAM17 expressions and clinical pathology was evaluated.RESULTSThe mRNA and expression profiles of TEX14 and ADAM17 were significantly elevated in CRC tissues. The positivity rates of TEX14 and ADAM17 proteins in CRC tissues were 70.93% and 77.91%, respectively. There were no significant differences in age, sex, pathological type, and tumor diameter between TEX14 and ADAM17-positive and -negative patients. Patients with higher tumor differentiation degree, deeper infiltration and TNM stages ranging from III to IV exhibited higher positivity rates of TEX14 and ADAM17. Patients with lymph node metastasis and distant metastasis showed higher positivity rates of TEX14 and ADAM17 than those without. Positive expressions of TEX14 and ADAM17 were highly correlated with tumor staging, invasion, and metastasis.CONCLUSIONTEX14 and ADAM17 profiles were significantly elevated in the CRC tissues of elderly patients, and their high expressions were associated with tumor staging, invasion, and metastasis.

Renal interstitial fibrosis (RIF) is a prevalent consequence of chronic renal diseases, characterized by excessive extracellular matrix (ECM) deposition. A Disintegrin and Metalloprotease 17 (ADAM17), a transmembrane metalloproteinase, plays a central role in driving renal fibrosis progression by activating Notch 1 protein and the downstream TGF-β signaling pathway. Our study investigated potential therapeutic interventions for renal fibrosis, focusing on human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs). We found that hucMSC-EVs inhibit ADAM17, thereby impeding renal fibrosis progression. Analysis of hucMSC-EVs miRNA profiles revealed significant enrichment of miR-13474, which effectively targeted and inhibited ADAM17 mRNA expression, subsequently suppressing Notch1 activation, TGF-β signaling, and collagen deposition. Overexpression of miR-13474 enhanced hucMSC-EVs' inhibitory effect on renal fibrosis, while its downregulation abolished this protective effect. Our findings highlight the efficacy of hucMSC-EVs overexpressing miR-13474 in mitigating renal fibrosis via ADAM17 targeting. These insights offer potential therapeutic strategies for managing renal fibrosis.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

The association of heart diseases with type 2 diabetes, especially myocardial infarction, calls for a search for biomarkers that have a relationship between the two. Which facilitates the process of reducing the development of myocardial infarction in patients with type 2 diabetes. The most prominent of these associations is long-term inflammation and its first and largest factor is interleukin 6, and its close association with A disintegrin and metalloprotease 17 (ADAM-17) and its inverse relationship with type 2 diabetic patients with and without myocardial infarction. This study aims to investigate the role of ADAM-17 in the pathogenesis of diabetic type 2 Iraqi men patients with and without MI by comparing them with a apparantely helthy as control group and to see their association with interleukin-6 levels and other biomarkers. The current study was conducted on 90 Iraqi men between Ja., 2023 and Aug. 2023, 60 samples with T2DM with or without MI and the remaining 30 as apparently healthy control. The patients were selected from the visitors of the coronary care unit (CCU) and Al-Hassan Center for Diabetes and Endocrinology in Kerbala, and they were diagnosed clinically and by laboratory investigations. Various biomarkers such as ADAM-17 and IL-6 have been determined by different biochemical techniques. As a result The highest ADAM-17 and IL-6 level in type 2 diabetes without myocardial infarction was seen as comparison serum levels of IL-6, and ADAM-17 for T2DM (with or without myocardial infarction) with the control group. The correlation between IL-6 and ADAM-17 is strong in type-2 diabetes without MI and between IL-6 and electrocardiogram represented by the two types STEM and NSTEMI in type-2 diabetes with MI. In conclusion, The current study found that ADAM-17 and IL-6 have a negative effect on chronic inflammation as in T2DM without MI is more severe than acute inflammation as T2DM with MI , du to elevation of ADAM-17 and IL-6 levels in type 2 diabetic patients without MI than type 2 diabetic patient with MI.

A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis factor (TNF) and cancer-implicated epidermal growth factor (EGF) family growth factors. iRhom2, a rhomboid-like, membrane-embedded pseudoprotease, is an essential cofactor of ADAM17. Here, we present cryoelectron microscopy (cryo-EM) structures of the human ADAM17/iRhom2 complex in both inactive and active states. These reveal three regulatory mechanisms. First, exploiting the rhomboid-like hallmark of TMD recognition, iRhom2 interacts with the ADAM17 TMD to promote ADAM17 trafficking and enzyme maturation. Second, a unique iRhom2 extracellular domain unexpectedly retains the cleaved ADAM17 inhibitory prodomain, safeguarding against premature activation and dysregulated proteolysis. Finally, loss of the prodomain from the complex mobilizes the ADAM17 protease domain, contributing to its ability to engage substrates. Our results reveal how a rhomboid-like pseudoprotease has been repurposed during evolution to regulate a potent membrane-tethered enzyme, ADAM17, ensuring the fidelity of inflammatory and growth factor signaling.

Purpose: Previous data have illustrated a role for the matrix metalloprotease A Disintegrin And Metalloprotease 17 (ADAM17), known to cleave growth factors and cytokines, in renal cell injury in diabetes. The goal of this study was to identify upstream regulators of ADAM17 in the cascade of events contributing to extracellular matrix accumulation in diabetic nephropathy. Rationale: Diabetic kidney disease is a serious complication faced by type 1 and type 2 diabetic patients alike. Albuminuria and extracellular matrix accumulation are prominent features of the disease and this accumulation of extracellular matrix is a contributing factor to renal fibrosis and decline in renal function. The mechanisms involved in the pathogenesis of diabetic kidney disease have not been completely identified. Methodology: Age and weight-matched Sprague Dawley rats were obtained from Harlan Laboratories (Indianapolis, IN). Type 1 diabetes was induced through tail vein injection of streptozotocin. After rats were determined to be diabetic by blood glucose measurement, rapamycin treatments were administered intraperitoneally for two months. Both kidneys were removed and frozen in liquid nitrogen for microscopy and experimental analyses or formalin fixed for morphometric imaging at the experimental endpoint. Kidney cortex homogenates were used for western blot analyses and enzymatic activity assays. Findings: Using the mTOR complex 1 inhibitor rapamycin, it was determined that increased ADAM17 enzymatic activity and ADAM17 protein expression is dependent on mTORC1 in streptozotocin-induced type 1 diabetic rats. Inhibition of mTORC1 with rapamycin abrogated the increase in collagen IV α 2 protein expression observed in diabetic rat cortex. Additionally, this study is the first to provide evidence that mTOR complex 1 activates ADAM17 contributing to extracellular matrix accumulation in diabetic nephropathy. Studies are continuing looking at the molecular mechanisms involved in mTOR activation of ADAM17 resulting in downstream effects in cultured human proximal tubular epithelial cells. Research reported in this poster was supported by the University of the Incarnate Word Offce of Research and Graduate Studies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BackgroundKawasaki disease (KD) is a pediatric systemic vasculitis characterized by endothelial cell dysfunction. Semaphorin 7A (Sema7A) has been reported to regulate endothelial phenotypes associated with cardiovascular diseases, while its role in KD remains unknown. This study aims to investigate the effect of Sema7A on endothelial permeability and inflammatory response in KD conditions.MethodsBlood samples were collected from 68 KD patients and 25 healthy children (HC). The levels of Sema7A and A Disintegrin and Metalloprotease 17 (ADAM17) in serum were measured by enzyme-linked immunosorbent assay (ELISA), and Sema7A expression in blood cells was analyzed by flow cytometry. Ex vivo monocytes were used for Sema7A shedding assays. In vitro human coronary artery endothelial cells (HCAECs) were cultured in KD sera and stimulated with Sema7A, and TNF-α, IL-1β, IL-6, and IL-18 of HCAECs were measured by ELISA and qRT-PCR. HCAECs monolayer permeability was measured by FITC-dextran.ResultsThe serum level of Sema7A was significantly higher in KD patients than in HC and correlated with disease severity. Monocytes were identified as one of the source of elevated serum Sema7A, which implicates a process of ADAM17-dependent shedding. Sera from KD patients induced upregulation of plexin C1 and integrin β1 in HCAECs compared to sera from HC. Sema7A mediated the proinflammatory cytokine production of HCAECs in an integrin β1-dependent manner, while both plexin C1 and integrin β1 contributed to Sema7A-induced HCAEC hyperpermeability.ConclusionsSema7A is involved in the progression of KD vasculitis by promoting endothelial permeability and inflammation through a plexin C1 and integrin β1-dependent pathway. Sema7A may serve as a potential biomarker and therapeutic target in the prognosis and treatment of KD.

Background: Growth factors are active substances secreted by a variety of cells, acting as messengers to regulate cell migration, proliferation or differentiation, which had important regulatory roles in the growth of individual cells, tissues or organs. Growth factors can regulate the proliferation and differentiation ability of cells, which keep the internal environment stable and affect the body size. Methods: In order to investigate the influence of the changes of growth factors contents on body size in Eothenomys miletus from Hengduan mountain regions, E. miletus in Dali (DL), Jianchuan (JC), Lijiang (LJ), Xianggelila (XGLL) and Deqin (DQ) were collected and their 7 morphological indicators and 9 growth factors, including insulin-like growth factor1 (IGF1), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), growth hormone release inhibitory factor (GRIF), platelet-derived growth factor (PDGF), transcription elongation factor1 (TCEA1), a disintegrin and metalloprotease17 (ADAM7), branched-chain amino acid transaminase1 (BCAT1), high mobility group protein1 (HMG1) were measured. Result: The results showed that body size of E. miletus among five regions had significant differentiated, body mass, body length, forelimb length, hind limb length, tail length, IGF, bFGF, EGF, PDGF, TCEA1 contents in DL, JC and LJ were greater than those of in XGLL and DQ and the contents of GRIF, ADAM7, BCAT1 and HMG1 were also different, decreasing with the increasing of regional latitude. Moreover, the increases in the contents of growth factors lead to the increase of body size in E. miletus, which does not support Bergman's law. Regional differences in body size of E. miletus in different regions may be related to the changes in body mass, morphological indicators and the content of growth factors. Moreover, growth factors may affect the body size of E. miletus by affecting the proliferation of bone, epidermis, muscle and differentiation of cells.