RIP2 plays a role in cardiac Ca2+ mishandling prompted by chronic kidney disease

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Specialized pro-resolving mediators prevents cardiac dysfunction by modulating Ca2+ handling and NRF2 axis

Trabajo presentado en el ESC Congress 2021 - The Digital Experience, celebrado en modalidad virtual el 27 de agosto de 2021

Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease

© 2020 by the authors.Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1−/− and Rip2−/− sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1−/−-Nx and Rip2−/−-Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.This work was supported by Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (SAF-2017-84777R), Institute of Health Carlos III (PI17/01093 and PI17/01344), Sociedad Española de Cardiología, Proyecto Traslacional 2019, Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII. M.F.-V. is Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). G.R.-H. is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). M.T. is a PhD student funded by the FPU program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135). A.R. was supported by Fondo SEP-Cinvestav project #601410 FIDSC 2018/2; and Fondo SEP-Conacyt Ciencia Básica A1-S-9082

Specialized proresolving mediators protect against experimental autoimmune myocarditis by modulating Ca2+ handling and NRF2 activation

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum–adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (SAF-2017-84777R), Instituto de Salud Carlos III (ISCIII) (PI17/01093, PI17/01344, and PI20/01482), Sociedad Española de Cardiología, Proyecto Traslacional 2019 and Asociación del Ritmo Cardiaco (SEC, España), Proyecto Asociación Insuficiencia Cardiaca (Trasplante Cardiaco) 2020, Fondo Europeo de Desarrollo Regional, Fondo Social Europeo, and CIBERCV, a network funded by ISCIII, Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 PID2020-113238RB-I00, PID2019-105600RB-I00, the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 [PT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed]), and “la Caixa” Foundation (project code HR17-00247). The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades. Dr Ruiz-Hurtado is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). Dr Tamayo and R.I. Jaén, and M. Gil-Fernández were or currently are PhD students funded by the Formación de Profesorado Universitario program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135; FPU16/00827, FPU1901973)

Under the Skin of a Lion: Unique Evidence of Upper Paleolithic Exploitation and Use of Cave Lion (Panthera spelaea) from the Lower Gallery of La Garma (Spain)

ABSTRACT: Pleistocene skinning and exploitation of carnivore furs have been previously inferred from archaeological evidence. Nevertheless, the evidence of skinning and fur processing tends to be weak and the interpretations are not strongly sustained by the archaeological record. In the present paper, we analyze unique evidence of patterned anthropic modification and skeletal representation of fossil remains of cave lion (Panthera spelaea) from the Lower Gallery of La Garma (Cantabria, Spain). This site is one of the few that provides Pleistocene examples of lion exploitation by humans. Our archaeozoological study suggests that lion-specialized pelt exploitation and use might have been related to ritual activities during the Middle Magdalenian period (ca. 14800 cal BC). Moreover, the specimens also represent the southernmost European and the latest evidence of cave lion exploitation in Iberia. Therefore, the study seeks to provide alternative explanations for lion extinction in Eurasia and argues for a role of hunting as a factor to take into account

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort

Background Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.Methods Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.Results Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.Conclusions During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis

Self-assembly of thermo and light responsive amphiphilic linear dendritic block copolymers

The synthesis and structural characterization of a new dual responsive linear-dendritic block copolymer (LDBC) is presented. The LDBC is constituted by a thermoresponsive linear block from polymethacrylate of oligo- and diethylene glycol, and a light responsive den- dron block of bis-MPA decorated at the periphery with 4-isobutyloxyazobenzene and alkyl chains in a 50:50 M ratio. Blocks are coupled together by copper(I) catalyzed alkyne–azide cycloaddition (CuAAC). The ability of the LDBC to form vesicle self-assemblies in water is described, as well as the effect of light and temperature on the vesicles morphology, on the basis of transmission electron microscopy (TEM), dynamic light scattering (DLS) and UV–vis spectroscopy studies. The effect of UV light and temperature on the vesicles struc- ture by SAXS and WAXS conducted on real time is also presented. Finally, the potential use of the vesicles to load and stimuli controlled release of small fluorescent molecules is probed

El FGF-23 altera la función contráctil e induce un fenotio proarritmogénico en el cardiomiocito adulto

Resumen del trabajo presentado a la 22ª Reunión Nacional de la Sociedad Española de Hipertensión - Liga Española para la Lucha contra la Hipertensión Arterial, celebrada en Madrid del 29 al 31 de marzo de 2017.[Objetivo]: La enfermedad cardiovascular y renal tiene a menudo orígenes similares y comparten factores de riesgo comunes. El factor de crecimiento de fibroblastos 23 (FGF-23) se está empezando a considerar en la actualidad como uno de los nuevos factores de riesgo no convencionales para el desarrollo de estas patologías. A nivel clínico, se ha descrito que FGF-23 está significativamente elevado en la enfermedad crónica renal. A nivel experimental, también se ha descrito que FGF-23 es capaz de inducir una hipertrofia del cardiomiocito aislado adulto. Sin embargo, es totalmente desconocido si FGF-23 puede o no ejercer un papel relevante sobre la función contráctil del cardiomiocito. El objetivo de este estudio es determinar si FGF-23 tiene algún efecto sobre el manejo del Ca2+ citosólico que pudiera condicionar la capacidad funcional de los cardiomiocitos.[Métodos]: Los cardiomiocitos adultos se obtuvieron de corazones de ratas machos, cepa Wistar (n = 9), mediante disociación enzimática con colagenasa tipo II por perfusión retrógrada en Langerdorf, y posterior disociación mecánica. El estudio del manejo del Ca2+ en el cardiomiocito se realizó mediante tinción con el colorante fluorescente Fluo-3AM y utilizando la microscopía confocal. Los cardiomiocitos aislados fueron perfundidos con 100 ng/ml de FGF-23 durante 2 minutos. La entrada de Ca2+ en los cardiomiocitos se estimó a través del análisis de la corriente de Ca2+ tipo L (ICaL) mediante técnicas de PatchClamp y bajo las mismas condiciones. Para estudiar la/s vía/s intracelular/es implicada/s en el efecto de FGF- 23, los cardiomiocitos fueron preincubados con el bloqueante del receptor de FGF-23 PD173074 (10 μmol/l) o con klotho soluble sklotho (100 ng/ml).[Resultados]: Los cardiomiocitos perfundidos con 100 ng/ml FGF-23 presentan una alteración en su función contráctil, con un empeoramiento significativo de la contracción (p < 0,01) y reducción de las velocidades tanto de contracción como de relajación (p < 0,05). Esta alteración viene asociada a una disminución acusada de los transitorios de Ca2+, y por tanto del Ca2+ sistólico. Esta reducción se debe tanto a una disminución de la corriente de entrada Ca2+ (ICaL) en los cardiomiocitos (p < 0,001) como a un enlentecimiento de la recaptación del Ca2+ itosólico al interior al retículo sarcoplásmico por la bomba ATPasa SERCA (p < 0,01). Además, cuando a los cardiomiocitos perfundidos con FGF-23 se les aplicaba un protocolo de diferentes estimulaciones eléctricas, éstos presentaban alteraciones proarritmogénicas caracterizadas por un incremento de la presencia de actividad desencadenada (p < 0,01) y un incremento de la liberación espontánea de Ca2+ a través de los denominados sparks y olas de Ca2+ en comparación con los cardiomiocitos perfundidos con vehículo (p < 0,01). Estas alteraciones fueron revertidas tanto por PD173074 como por sklotho (p < 0,01).[Conclusiones]: Este estudio demuestra por primera vez que FGF-23 altera de forma muy relevante el manejo del Ca2+ intracelular en el cardiomiocito adulto, provocando una importante alteración en su función contráctil. Por otro lado, FGF-23 induce un fenotipo proarritmogénico en los cardiomiocitos el cual se previene en presencia de s-Klotho. Estos efectos provocados por FGF-23 sobre el cardiomiocito podrían explicar las alteraciones funcionales cardiacas que presentan los pacientes con enfermedad renal.Peer Reviewe