Epigenética en la enfermedad renal: Investigación de las proteínas BET como potenciales dianas terapéuticas

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 06-04-201

Bromodomain and extraterminal proteins as vovel epigenetic targets for renal diseases

Epigenetic mechanisms, especially DNA methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. The bromodomain and extraterminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. Experimental data have demonstrated the involvement of some BET proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. Selective bromodomain inhibitors are epigenetic drugs that block the interaction between BET proteins and acetylated proteins, thus exerting beneficial effects. Recent data have described the beneficial effect of BET inhibition on experimental renal diseases. Emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (CKD). Several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in CKD patients. Here, we review how targeting bromodomains in BET proteins may regulate essential processes involved in renal diseases and in associated complications found in CKD patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against BET proteins for CKD treatment and associated risksThis work was supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119; Red de Investigación Renal REDINREN: RD16/0009 and PI17/01244), Sociedad Española de Nefrología and “NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento”; B2017/BMD- 3751, Comunidad de Madrid. The “Juan de la Cierva Formacion” training program of the Ministerio de Economia, Industria y Competitividad supported the salary of SR-M (FJCI-2016-29050

ECOGENIO: un juego de Instagram para descubrir y valorar la Economía y la Empresa

Memoria ID2022-140 Ayudas de la Universidad de Salamanca para la innovación docente, curso 2022-2023

Management Pearls on the Treatment of Actinic Keratoses and Field Cancerization

Field cancerization (FC) is a chronic disease involving multiple clinical and subclinical actinic keratoses (AK) on large photo-exposed surfaces with multifocal areas of dysplasia and precancerous changes. Patients and treatment must be properly monitored and managed to avoid aggravation and progression of the disease. Management of actinic keratoses includes lesion-directed treatments, such as cryotherapy and field-directed therapies. Field-directed therapies may have the potential to address subclinical damage, reduce AK recurrence rates and potentially reduce the risk of squamous cell carcinoma development. Multiple studies have demonstrated the efficacy of field-directed treatments, including 5-fluorouracil, photodynamic therapy, imiquimod, chemical exfoliation with trichloroacetic acid and diclofenac gel, for multiple AK and FC. The choice of therapy should be based on multiple factors, such as efficacy, tolerability, patient risk profile, costs and cosmetic results. Management of AK includes not only treatment but also prevention. Medical devices, such as sunscreens containing liposome-encapsulated DNA repair enzymes, can repair DNA damage associated with chronic UV radiation and reduce the number of new AK lesions. Here we provide therapeutic pearls and expert opinions on the treatment of AK and FC (as monotherapy or in combination) with the overall aim to achieve better, faster, and well-tolerated clinical responses

Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

Chronickidneydisease (CKD)ischaracterized bypersistent inflammationandprogressive fibrosis,ultimatelyleadingto end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.This work was supported by the Instituto de Salud Carlos III and Fondos FEDER European Union (PI014/00041, PI17/00119), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), and Sociedad Española de Nefrología. The “Juan de la Cierva de Formacion” training program of the Ministerio de Economía, Industria y Competitividad, Gobierno de España supported the salary of SR-M (FJCI-2016-29050)

Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology

The growing incidence of obesity, hypertension, and diabetes, coupled with the aging of the population, is increasing the prevalence of renal diseases in our society. Chronic kidney disease (CKD) is characterized by persistent inflammation, fibrosis, and loss of renal function leading to end-stage renal disease. Nowadays, CKD treatment has limited effectiveness underscoring the importance of the development of innovative therapeutic options. Recent studies have identified how epigenetic modifications participate in the susceptibility to CKD and have explained how the environment interacts with the renal cell epigenome to contribute to renal damage. Epigenetic mechanisms regulate critical processes involved in gene regulation and downstream cellular responses. The most relevant epigenetic modifications that play a critical role in renal damage include DNA methylation, histone modifications, and changes in miRNA levels. Importantly, these epigenetic modifications are reversible and, therefore, a source of potential therapeutic targets. Here, we will explain how epigenetic mechanisms may regulate essential processes involved in renal pathology and highlight some possible epigenetic therapeutic strategies for CKD treatment.This work was supported by Instituto de Salud Carlos III and Fondos FEDER European Union (PI14/00041, PI15/00960, PI16/01354, PI17/00119, and PI17/01244), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), Fondecyt 1181574 (BK), Sociedad Española de Nefrología, and the “Juan de la Cierva Formacion” training program of the Ministerio de Economia, Industria y Competitividad which supported the salary of S.R-M (FJCI-2016-29050). V. Marchant has a CONICYT Scholarship for his graduate studies at the PhD program in Medical Science, Universidad Austral de Chile. The Centro de Estudios Científicos is funded by the Chilean Government through the Centers of Excellence Basal Financing Program of CONICYT

CCN2 Binds to Tubular Epithelial Cells in the Kidney

Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR). Moreover, CCN2(IV) activates proinflammatory and profibrotic responses in the mouse kidney. The aim of this paper was to locate the in vivo cellular CCN2/EGFR binding sites in the kidney. To this aim, the C-terminal module CCN2(IV) was labeled with a fluorophore (Cy5), and two different administration routes were employed. Both intraperitoneal and direct intra-renal injection of Cy5-CCN2(IV) in mice demonstrated that CCN2(IV) preferentially binds to the tubular epithelial cells, while no signal was detected in glomeruli. Moreover, co-localization of Cy5-CCN2(IV) binding and activated EGFR was found in tubules. In cultured tubular epithelial cells, live-cell confocal microscopy experiments showed that EGFR gene silencing blocked Cy5-CCN2(IV) binding to tubuloepithelial cells. These data clearly show the existence of CCN2/EGFR binding sites in the kidney, mainly in tubular epithelial cells. In conclusion, these studies show that circulating CCN2(IV) can directly bind and activate tubular cells, supporting the role of CCN2 as a growth factor involved in kidney damage progression

Low Phase Angle Values Are Associated with Malnutrition according to the Global Leadership Initiative on Malnutrition Criteria in Kidney Transplant Candidates : Preliminary Assessment of Diagnostic Accuracy in the FRAILMar Study

Malnutrition has a negative impact on patients with chronic diseases and its early identification is a priority. The primary objective of this diagnostic accuracy study was to assess the performance of the phase angle (PhA), a bioimpedance analysis (BIA)-derived parameter, for malnutrition screening using the Global Leadership Initiative for Malnutrition (GLIM) criteria as the reference standard in patients with advanced chronic kidney disease (CKD) waiting for kidney transplantation (KT); criteria associated with low PhA in this population were also analyzed. Sensitivity, specificity, accuracy, positive and negative likelihood ratios, predictive values, and area under the receiver operating characteristic curve were calculated for PhA (index test) and compared with GLIM criteria (reference standard). Of 63 patients (62.9 years old; 76.2% men), 22 (34.9%) had malnutrition. The PhA threshold with the highest accuracy was ≤4.85° (sensitivity 72.7%, specificity 65.9%, and positive and negative likelihood ratios 2.13 and 0.41, respectively). A PhA ≤ 4.85° was associated with a 3.5-fold higher malnutrition risk (OR = 3.53 (CI95% 1.0-12.1)). Considering the GLIM criteria as the reference standard, a PhA ≤ 4.85° showed only fair validity for detecting malnutrition, and thus cannot be recommended as a stand-alone screening tool in this population

Juntos hacemos facultad: nueva estrategia de promoción y comunicación de las titulaciones ofertadas por la Facultad de Economía y Empresa de la Universidad de Salamanca

Memoria ID-132. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020.[ES]Con el presente proyecto se pretende dar una mayor promoción y visibilidad a las diferentes acciones de la Facultad de Economía y Empresa, lanzando también nuevas líneas de actuación en función de las diferentes oportunidades y amenazas detectadas en el entorno y potenciando los vínculos entre la enseñanza universitaria, la preuniversitaria, instituciones internacionales y nuestro entorno empresarial y social más cercan

An Aptamer against MNK1 for Non-Small Cell Lung Cancer Treatment

Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment.R.C.-M. was supported for predoctoral contracts (PEJD 2016-BMD-2145 and 2018-BMD-9201) from the Community of Madrid and grant RTC2019-07227-1. M.E.M. and V.M.G. are researchers from FIBio-HRC supported by Consejeria de Sanidad (CAM). This work was supported by grants RTC2019-07227-1 and PID2019-105417RB-I00, funded by MCIN/AEI/10.13039/501100011033 (Ministry of Economy and Competitiveness, Spain)