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Rheumatoid arthritis (RA) patients might experience anxiety and depressive symptoms. Deficient vitamin D levels may be a trigger for these conditions. The aim of this study was to determine the frequency of depression, anxiety symptoms, and suicidal risk or ideation in patients with RA associated with vitamin D serum levels.In this cross-sectional study, we recruited RA patients older than 18 years, classified into 3 groups according to serum vitamin D levels: sufficient, ≥30 ng/mL; insufficient, 20-29 ng/mL; and deficient,20 ng/mL. Based on the self-reported Plutchik and the Hospital Anxiety and Depression Scale, we evaluated the association of suicidal risk, depression, and anxiety with the vitamin D levels in RA and the Rheumatoid Arthritis Quality-of-Life Questionnaire.We studied 72 patients with RA between January and October 2019. We found an inverse correlation between Plutchik score and suicidal risk with inadequate vitamin D levels, but not with the Hospital Anxiety and Depression Scale. Suicidal ideation was associated with a higher score on the Rheumatoid Arthritis Quality-of-Life Questionnaire.Despite the high prevalence of depressive and anxiety symptoms in RA patients, a Plutchik low correlation coefficient with inadequate serum levels of vitamin D was found. However, in the analysis of covariance, we were able to find that vitamin D levels remain associated with a reduction of suicide ideation. Further studies are needed to identify a risk profile for early psychological interventions to improve the quality of life in RA patients.

The rise in demand for more FAIR (Findable, Accessible, Interoperable, and Reusable) data is being answered by increasingly automated ways to capture, process, publish and register biodiversity datasets. Coupled with the increasing possibilities for detecting hundreds of species in a single sample/event (i.e., eDNA), this results in taxonomic information that is multiple levels of magnitude higher than it was a couple of years ago. This spike in content has an adverse effect on the ability of researchers to find relevant datasets within catalogues, due to the limitations in storing and displaying the taxonomic metadata (e.g., in the real-estate of a webpage, in the timeframe required to access the quantity of information, in displaying information to users in a comprehensive and comprehensible way). WoRMS (World Register of Marine Species) is a taxonomic backbone that provides species information. One user of WoRMS is the Integrated Marine Information System (IMIS), a metadata catalogue for marine data, which is also the metadata catalogue of the European node of the Ocean Biodiversity Information System (EurOBIS). Taxonomic information added to the metadata records in IMIS are linked to WoRMS Persitent Identifiers or PIDs (AphiaIDs). Tension between providing all the taxonomic metadata while not overloading the catalogue is being addressed for the use-case of WoRMS+IMIS+EurOBIS. Our approach is to apply a filter-and-replace algorithm during the automated registration of the taxonomic metadata to describe available datasets. This technique reduces the detailed taxonomic information of actual occurrences in the dataset content into practical (good enough) metadata. It takes as input all the species in the dataset along with their hierarchical structure, as well as a configuration parameter allowing for an upper bound to the acceptable number of taxa to be output. The core principle of the algorithm is to start off with the minimal result set containing only the hierarchical root (always "biota") of the complete taxonomy in the dataset, and then to gradually consider replacing each element with its children one level deeper, as long as that replacement keeps fitting the upper bound for the total set. This approach ensures that no coverage is lost, meaning every taxon in the actual dataset is represented in the result, although possibly through one of its parents, X layers up. Note that as long as only one child is underlying, the switch will always happen. So by nature, it will go down to the lowest relevant detail without challenging the upper bound limit. It also allows for variation in the actual processing by allowing for different ordering strategies on the current result-set. Ordering strategies under test are: Order (descending) by weight of underlying available children → favouring more detail in those parts of the tree that have the most members in the setWith weight defined as the count of all underlying available species, ORWeight defined as the sum-product of those species with their actual occurrences in the dataset (thus further favouring detail to those parts of the tree that are more prevalent in the samples) Order (descending) by number of direct children → favouring fanning-out over available high-level siblings Order (ascending) by ratio of present children over available children in the taxa → favouring replacing too vague parents with the more specific sublevels that are actually in the dataset Order (descending) by weight of underlying available children → favouring more detail in those parts of the tree that have the most members in the setWith weight defined as the count of all underlying available species, ORWeight defined as the sum-product of those species with their actual occurrences in the dataset (thus further favouring detail to those parts of the tree that are more prevalent in the samples) With weight defined as the count of all underlying available species, OR Weight defined as the sum-product of those species with their actual occurrences in the dataset (thus further favouring detail to those parts of the tree that are more prevalent in the samples) Order (descending) by number of direct children → favouring fanning-out over available high-level siblings Order (ascending) by ratio of present children over available children in the taxa → favouring replacing too vague parents with the more specific sublevels that are actually in the dataset Alongside this basic approach, additional pre-processing of the taxa in the dataset can apply some form of "pruning". In this approach all nodes in the available taxon tree of the dataset are ordered (descending) by the weight of underlying children, and those at the end—below some defined cutoff ratio (extra parameter to the algorithm)—are simply discarded. Again, the interpretation of this weight (only species count, or multiplied by occurrence count) yields to variants of the algorithm to be tested. Applying this pruning means a deliberate departure is taken from the full-coverage guarantee mentioned earlier. Caution should be applied, of course, but removing more irrelevant (low occurrence) parts of the tree will allow for making space in the bounded result-set for more detail in the parts that are relevant. In order to create an objective basis for comparing the resulting variants, a number of "qualification" parameters are considered to quantify the effect of the suggested reduction. Based on the datasets in EurOBIS, the variants of this algorithm are being applied and results will be presented on how they affect the various qualification parameters. It is worth observing that both datasets and their metadata records are distinct resources that are being linked to species (taxa references) and that the different purposes they serve require different levels of detail to be presented. As other types of entities (publications, habitats, experts, geography, traits, etc.) are considered for linking to species, we believe similar reduction algorithms will be necessary.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immunesystem, predominantly Th17 and lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and in target organ damage. Preclinical studiesin mice have shown that systemic adminstration of IL-17A increases blood pressure, prob-ably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are alreadyelevated in patients with mild or moderate hypertension. Many studies in hypertensive mice models have detected IL-17A-producing cells in target organs such as the heart, vesselsand kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17lymphocytes and lymphocytes that express IL-17A. In addition, in experimental models ofhypertension, the blockade of IL-17A by genetic strategies or using neutralizing antibodies,disminished blood pressure, probablyby acting on the small mesenteric arteries as well as inthe regulation of tubule sodium transport. Moreover, IL-17A inhibition reduces end-organsdamage. As a whole, the data presented in this review suggest that IL-17A participates in theregulation of blood pressure and in the genesis and maintenance of arterial hypertension,and may constitute a therapeutic target of hypertension-related pathologies in the future. La interleuquina 17A (IL-17A) es una citoquina proinflamatoria producida por células del sis-tema inmune, sobre todo por los linfocitos Th17 y los linfocitos . En este trabajo, revisamosel papel de IL-17A en la patogenia de la hipertensión y de la lesión en órganos diana. Estu-dios en ratones han demostrado que la IL-17A aumenta la presión arterial, probablementepor acciones a varios niveles. Además, las concentraciones plasmáticas de IL-17A están yaaumentadas en pacientes con hipertensión arterial ligera o moderada. Estudios preclíni-cos sobre hipertensión arterial han detectado células productoras de IL-17A en órganosdiana, como corazón, vasos y ri ̃nón. En pacientes con nefroesclerosis hipertensiva existeinfiltración del ri ̃nón por linfocitos Th17 y linfocitos que expresan IL-17A. Además, enmodelos experimentales de hipertensión el bloqueo de IL-17A, mediante estrategias génicas,o utilizando anticuerpos neutralizantes, disminuye la presión arterial por acciones sobre lapared vascular y el transporte tubular de sodio y disminuye la lesión en órganos diana. Enconjunto, los datos presentados en esta revisión sugieren que la IL-17A participa en la reg-ulación de la presión arterial y en la génesis y mantenimiento de la hipertensión arterial,pudiendo constituir una diana terapéutica en el futuro. This work has been funded by the Spanish Society of Nephrology and by grants from the Carlos III Health Institute (ISCIII) and FEDER European Union Funds (PI17/00119 and PI20/00140 and Renal Research Network (REDINREN): RD16/0009, to MR-O, RS, PI17/01495 to JE), Community of Madrid («NOVELREN» B2017/BMD3751 to MR-O); the José Castillejo grant (CAS19/00133 to RRR-D); «Juan de la Cierva Incorporacion» of the Ministry of Economy, Industry and Competitiveness (MINECO) for SR-M (IJC2018-035187-I); “Call for Dynamization Europe Research 2019” MINECO (EIN2019-103294 to MR-O and SR-M); IMPROVE-PD project («Identification and Management of Patients at Risk – Outcome and Vascular Events in Peritoneal Dialysis») of Horizon 2020 MarieSkłodowska-Curie Grant Agreement No. 812699 to MRO, and Fondecyt Chile 1160465

Background and aims Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. Approach and results This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174-0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. Conclusions A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.

BACKGROUND AND AIMS Peritoneal dialysis (PD) is the current replacement therapy for end-stage renal disease (ESRD) patients until renal transplantation can be achieved. However, chronic exposure to non-physiological PD fluids (PDF) and occasional infection episodes may lead to peritoneal damage and membrane transport failure. Chronic inflammation, together with mesothelial-to-mesenchymal transition (MMT) and submesothelial fibrosis, is a hallmark of PDF-associated peritoneal damage whose intrinsic mechanisms are still expected to be disclosed [1–2]. Activation of the innate immunity is the cornerstone for infectious agents’ elimination, also enrolled in response to damage-associated molecular patterns (DAMPs) released from stressed or injured host cells. Leakage of DNA from stressed mitochondria and damaged genomic DNA may act as DAMPs that are recognized by cytosolic double-strand DNA sensors, like the stimulator of interferon gene (STING), to mount an inflammatory response [3]. Excessive activation of STING is involved in autoinflammatory, autoimmune, and increasingly related to several chronic inflammatory conditions [4]. Thus, this study aimed to investigate the role of STING in experimental peritoneal damage. METHOD We induced peritoneal fibrosis in wild-type and STING-KO mice by intraperitoneal administration of 0.1% chlorhexidine gluconate (CHX) daily for 4 weeks. No treated WT and STING-KO mice were used as control. Then, mice were euthanized, and peritoneal tissue and peritoneal lavage fluids were recollected for the following experiments. STING mRNA (Tmem173) and protein levels in control and CHX-treated wild-type were measured by RT-qPCR, western blot and immunohistochemistry. Peritoneal levels of the STING downstream proteins TBK1 and IRF3 and their phosphorylated isoforms were assayed by western blot. Peritoneal membrane thickness was measured in formalin-fixed paraffin-embedded tissues stained with Masson's trichrome stain. Fibronectin protein levels were evaluated by western blot and MMT, fibrosis, and inflammation markers were determined by RT-qPCR. Inflammatory cells present in peritoneal effluents were assayed by flow cytometry. RESULTS We found that in the peritoneum of CHX-treated wild-type mice both Tmem173 expression and STING protein levels were increased. Interestingly, STING-positive cells were located in areas of peritoneal thickness and immune infiltration. Moreover, the protein levels of IRF3, p-IRF3, TBK1 and p-TBK1 were increased, indicating that the STING pathway is activated in experimental peritoneal damage. In STING-KO mice, CHX-induced peritoneal damage was prevented. STING-KO mice under CHX treatment showed decreased peritoneal membrane thickness and attenuated CHX-induced expression of fibrosis and MMT markers, such as Tgb1, Snai1, Cdh2, Col1a1, Fn1 and fibronectin protein when compared with CHX-treated WT mice. The absence of STING also prevented the gene expression of cytokines (Il1b, Il6 and Ifng) and chemokines (Ccl5, Ccl2 and Ccl19) and macrophages infiltration into the peritoneum. Inflammatory cell recruitment into the peritoneal cavity was also decreased in STING-KO mice, including CD3+CD4+ lymphocytes and CD11b+F4/80+ macrophages. CONCLUSION In summary, STING absence prevents peritoneal membrane thickness, fibrosis, and inflammation induced by CHX in a mice model. These results suggest that STING plays a key role in peritoneal membrane injury. Therefore, STING may become a new potential therapeutic target in PD-associated peritoneal damage.

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor β (TGF-β). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-β together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet. Considering the main role of TGF-β receptors (TβR) in the TGF-β pathway activation, our aim was to investigate the effects of CCN2 in the regulation of TβRI and TβRII levels in vascular smooth muscle cells (VSMCs). While no differences were observed in TβRI levels, an increase in TβRII expression at both gene and protein level were found 48 h after stimulation with the C-terminal fragment of CCN2 (CCN2(IV)). Cell pretreatment with a TβRI inhibitor did not modify TβRII increment induced by CCN2(VI), demonstrating a TGF-β-independent response. Secondly, CCN2(IV) rapidly activated the SMAD pathway in VSMCs, this being crucial in the upregulation of TβRII since the preincubation with an SMAD3 inhibitor prevented it. Similarly, pretreatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib abolished TβRII upregulation, indicating the participation of this receptor in the observed responses. Our findings suggest a direct role of CCN2 maintaining the TGF-β pathway activation by increasing TβRII expression in an EGFR-SMAD dependent manner activation.

Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence-associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction.

BACKGROUND AND PURPOSE Hepatitis C virus (HCV) infection is associated with neuropsychiatric disturbances that impact on functioning and health-related quality of life (HRQoL). Reversibility at different liver disease stages is unknown, particularly in cirrhosis. We aimed to evaluate cognition, functioning, and HRQoL following HCV eradication at different liver disease stages. METHODS A random sample (n = 152) of consecutive patients treated with direct-acting antiviral agents (DAAs) between April 2015 and March 2017 were included. A comprehensive neuropsychological assessment, functioning and HRQoL questionnaires were applied at baseline, and 12 and 48 weeks after the end of antivirals. RESULTS One-hundred thirty-five patients who achieved virological response completed the follow-up, of whom 44 had cirrhosis (27% decompensated). Twenty-one percent had cognitive impairment before starting DAAs (34.1% cirrhotic vs. 14.4% noncirrhotic, p

Background and Aims Acute kidney injury (AKI) is associated with elevated mortality and morbidity presenting higher frequency in aged patients. Different mechanisms are activated in AKI, including tubular epithelial cell death (apoptosis and regulated necrosis), inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest (or cellular senescence). There is a strong connection between pathways activated in AKI and development of cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular mechanisms in ageing-associated mortality are not completely understood. Our aim was to investigate age-related molecular mechanisms of AKI. Method Experimental nephropathy by folic acid administration (FA, 125mg/kg) was induced in young (3 months) and old (12 months) mice. Renal lesions and mechanisms were evaluated at 48 hours (AKI acute phase). Results AKI mortality was higher in old (50 %) than in young (15%) mice 4 days after FA injection (pilot study). Tubular damage score (PAS evaluation) and KIM-1 tubular expression (renal damage biomarker) were also higher in old than in young FA-injected mice after 48h. The number of infiltrating immune cells (mainly neutrophils and macrophages) and gene expression levels of proinflammatory genes (Lcn-2 and ccl2) were significantly higher in FA kidneys of old as compared to young mice. Regulated necrosis (necroptosis), contrary to apoptosis, induces an inflammatory response and necroinflammation, being macrophages the key effector immune cells of this cell death pathway. Among some of the key necroptosis mediators, MLKL and RIPK3 were higher in old FA kidneys. These data could indicate a magnification of the inflammatory response to AKI in older mice. In contrast, expression of protective factors was dramatically downregulated in old FA mice, including the mitochondrial biogenesis driver PGC-1α, and the antiaging factor Klotho. Cellular senescence was induced in FA kidneys, as indicated by increased levels of cyclin-dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA Damage Response marker yH2AX. Importantly, p21 mRNA expression and nuclear staining for p21 and yH2AX were increased in FA kidneys, and the fold increase was significantly higher in old than in young mice. Also, the expression of senescence-associated secretory phenotype (SASP) components (Tgfb1, Il-6, and Serpine-1) was significantly higher in old FA mouse kidneys. Interestingly, also some infiltrating immune cells were p21/yH2AX positive, suggesting molecular senescence in the immune cells (“immunesenescence”) and inflammation in the ageing kidney (“inflammaging”) are involved in the aggravated AKI response to FA in old mice. Conclusion Our data indicate that in advanced age, exposure to toxic compounds results in a more severe AKI response that might relate to an early inflammatory response characterize by more extensive necroptosis and activation of pathways related to cellular senescence of resident kidney cells and infiltrating inflammatory cells.

Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney injury (AKI). Therefore, finding antifibrotic therapies comprises an intensive research field in Nephrology. Nowadays, ECM is not only considered as a cellular scaffold, but also exerts important cellular functions. In this review, we describe the cellular and molecular mechanisms involved in kidney fibrosis, paying particular attention to ECM components, profibrotic factors and cell–matrix interactions. In response to kidney damage, activation of glomerular and/or tubular cells may induce aberrant phenotypes characterized by overproduction of proinflammatory and profibrotic factors, and thus contribute to CKD progression. Among ECM components, matricellular proteins can regulate cell–ECM interactions, as well as cellular phenotype changes. Regarding kidney fibrosis, one of the most studied matricellular proteins is cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), currently considered as a fibrotic marker and a potential therapeutic target. Integrins connect the ECM proteins to the actin cytoskeleton and several downstream signaling pathways that enable cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. In kidney fibrosis, there is an increase in ECM deposition, lower ECM degradation and ECM proteins cross-linking, leading to an alteration in the tissue mechanical properties and their responses to injurious stimuli. A better understanding of these complex cellular and molecular events could help us to improve the antifibrotic therapies for CKD.

Molecules, e-ISSN 1420-3049 , 2021, 26, 5606 Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immune system, predominantly Th17 lymphocytes and γδ lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and target organ damage. Studies in mice have shown that IL-17A increases blood pressure, probably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are already elevated in patients with mild or moderate hypertension. Preclinical studies on arterial hypertension have detected IL-17A-producing cells in target organs such as the heart, vessels and kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17 lymphocytes and γδ lymphocytes that express IL-17A. In addition, in experimental models of hypertension, blocking IL-17A by genetic strategies, or using neutralising antibodies, lowers blood pressure by acting on the vascular wall and tubule sodium transport and reduces damage to target organs. As a whole, the data presented in this review suggest that IL-17A participates in the regulation of blood pressure and in the genesis and maintenance of arterial hypertension, and may constitute a therapeutic target in the future.

This is the peer reviewed version of the following article: "Statins: Could an old friend help the fight against COVID-19?" . British Journal of Pharmacology (2020): 19 June, which has been published in final form at https://doi.org/10.1111/bph.15166. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions, he COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID-19 outcomes, This work and data discussed here were supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119 and Red de Investigación Renal (REDINREN): RD16/0009, to M.R-O, PI17/01495 to J.E, PI18/01133 to AMR, PI19/00815 to A.O); Comunidad de Madrid (“NOVELREN” B2017/BMD3751 to M.R-O, B2017/BMD-3686 CIFRA2-CM to A.O); Spanish Ministry of Economy and Competitiveness MINECO (DTS17/00203, DTS19/00093) to J,E; “Convocatoria Dinamización Europa Investigación 2019” MINECO (EIN2019-103294 to M.R-O and SR-M); ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071) and DTS18/00032 to A.O; The “Sara Borrell” postdoctoral training program of the ISCIII supported the salary of SR-M (CD19/00021), IMPROVE-PD project (“Identification and Management of Patients at Risk–Outcome and Vascular Events in Peritoneal Dialysis”) funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 812699 to M.R.O.

Gremlin is a member of the TGF-β superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.

Gremlin is a member of the TGF-β superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.

Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy. This work and data discussed here were supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119 and Red de Investigacion Renal (REDINREN): RD16/0009, to M.R.-O., PI17/01495, DTS17/00203 and DTS19/00093 to J.E., PI16/02057, PI19/00815 to A.O.); Comunidad de Madrid ("NOVELREN" B2017/BMD-3751 to M.R.-O., B2017/BMD-3686 CIFRA2-CM to A.O.); the Jose Castillejo grant (CAS19/00133 to R.R.R.-D.); the "Juan de la Cierva Formacion" training program of the Ministerio de Economia, Industria y Competitividad (MINECO) supported the salary of S.R.-M. (FJCI-2016-29050); "Convocatoria Dinamizacion Europa Investigacion 2019" MINECO (EIN2019-103294 to M.R.-O. and S.R.-M.); Sociedad Espanola de Nefrologia (S.E.N. to M.R.-O.). Grants Fondecyt 1160465 to S.M. and PAI 82140017 to C.L. of Chile; ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071) and DTS18/00032 to A.O.; IMPROVE-PD project ("Identification and Management of Patients at Risk-Outcome and Vascular Events in Peritoneal Dialysis") funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 812699 to M.R.O.

Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response., MINECO | Instituto de Salud Carlos III (ISCIII), Grant/Award Number: PI17/00119; Ministerio de Economia y Competitividad, Grant/Award Number: SAF2015-66107-R; Comunidad Autonoma de Madrid, Grant/Award Number: B2017/ BMD-3751; Fondo Nacional de Desarrollo

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR‐9‐5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro‐fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor‐beta 1 (TGF‐β1)‐dependent de‐differentiation in human kidney proximal tubular (HKC‐8) cells. RNA‐sequencing (RNA‐Seq) studies in the UUO model revealed that treatment with miR‐9‐5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR‐9‐5p impeded TGF‐β1‐induced bioenergetics derangement. The expression of the FAO‐related axis peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC‐1α)‐peroxisome proliferator‐activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR‐9‐5p. We found that in mice null for the mitochondrial master regulator PGC‐1α, miR‐9‐5p was unable to promote a protective effect in the UUO model. We propose that miR‐9‐5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells., This work was supported by Grants from the Ministerio de Economía y Competitividad (MINECO) SAF 2012‐31388 (SL) and SAF2015‐66107‐R (SL), both cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL and MRO), PI17/00119 (MRO), SAF2015‐63904‐R (MM), cofunded by the European Regional Development Fund, European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement 721236‐TREATMENT (MM), Comunidad de Madrid “NOVELREN” B2017/BMD­3751 (SL and MRO), and Fundación Renal “Iñigo Alvarez de Toledo” (SL), all from Spain. The CBMSO receives institutional support from Fundación “Ramón Areces”. VM and CNT were supported by predoctoral fellowships of the FPI Program (BES‐2013‐065986 and BES‐2014‐068929) from MINECO.