The contribution of histone crotonylation to tissue health and disease: focus on kidney health

Acute kidney injury (AKI) and chronic kidney disease (CKD) are the most severe consequences of kidney injury. They are interconnected syndromes as CKD predisposes to AKI and AKI may accelerate CKD progression. Despite their growing impact on the global burden of disease, there is no satisfactory treatment for AKI and current therapeutic approaches to CKD remain suboptimal. Recent research has focused on the therapeutic target potential of epigenetic regulation of gene expression, including non-coding RNAs and the covalent modifications of histones and DNA. Indeed, several drugs targeting histone modifications are in clinical use or undergoing clinical trials. Acyllysine histone modifications (e.g. methylation, acetylation, and crotonylation) have modulated experimental kidney injury. Most recently, increased histone lysine crotonylation (Kcr) was observed during experimental AKI and could be reproduced in cultured tubular cells exposed to inflammatory stress triggered by the cytokine TWEAK. The degree of kidney histone crotonylation was modulated by crotonate availability and crotonate supplementation protected from nephrotoxic AKI. We now review the functional relevance of histone crotonylation in kidney disease and other pathophysiological contexts, as well as the implications for the development of novel therapeutic approaches. These studies provide insights into the overall role of histone crotonylation in health and diseaseSources of support: FIS/FEDER funds (PI15/00298, CP14/00133, PI16/02057, PI16/01900, PI18/01386, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD- 3686 CIFRA2-CM. Salary support: ISCIII Miguel Servet and to AS and MS-N, ISCIII Sara Borrell to JM-M and Comunidad de Madrid (B2017/BMD-3686 CIFRA2-CM) to MF-B and DM-S

Espacio y territorios: razón, pasión e imaginarios

En este caleidoscopio de acercamientos hacia lo espacial y territorial, las visiones se mueven desde aquellas románticas y existencialistas, pasando por aquellas objetivistas y positivistas, hasta las estructuralistas y postestructuralistas. Por el espacio y el territorio se interesan con enfoques diversos numerosas disciplinas, desde la psicología, la etología o la literatura, y las ciencias naturales como la biología o la ecología, hasta las ciencias sociales y políticas, como la geografía, la antropología, la economía y la sociología. Este interés multidisciplinario demuestra la importancia y la complejidad del tema espacial y territorial, y reclama la necesidad de su estudio y comprensión interdisciplinarios, como se intenta con esta publicación

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury

Studies of mitochondria-targeted nephroprotective agents suggest a key role of mitochondrial injury in AKI. Here we tested whether an improved perception of factors responsible for mitochondrial biogenesis may provide clues to novel therapeutic approaches to AKI. TWEAK is an inflammatory cytokine which is upregulated in AKI. Transcriptomic analysis of TWEAK-stimulated cultured murine tubular epithelial cells and folic acid-induced AKI in mice identified downregulation of peroxisome proliferator- activated receptor-γ coactivador-1α (PGC-1α) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature. Neutralizing anti-TWEAK antibodies prevented the decrease in kidney PGC-1α and its targets during AKI. TWEAK stimulation decreased kidney PGC-1α expression in healthy mice and decreased expression of PGC-1α and its targets as well as mitochondrial membrane potential in cultured tubular cells. Adenoviral-mediated PGC-1α overexpression prevented TWEAK-induced downregulation of PGC-1α-dependent genes and the decrease in mitochondrial membrane potential. TWEAK promoted histone H3 deacetylation at the murine PGC-1α promoter. TWEAK-induced downregulation of PGC-1α was prevented by histone deacetylase or NF-κB inhibitors. Thus, TWEAK decreases PGC-1α and target gene expression in tubular cells in vivo and in vitro. Approaches that preserve mitochondrial function during kidney injury may be therapeutic for AKI.This study was supported by ISCIII and FEDER funds PI13/00047, PIE13/00051, EUTOX, CP12/03262, CP14-00133, FRIAT Sociedad Española de Nefrología, ISCIII-RETIC REDinREN RD012/0021, and Comunidad de Madrid CIFRA S2010/BMD-2378. The salary support was as follows: F.P.U. to OR-A, ISCIII Miguel Servet MS12/03262 to ABS and MS14/00133 MDS-N, and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO.Peer Reviewe

PGC-1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI

PGC‐1α (peroxisome proliferator‐activated receptor gamma coactivator‐1α, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC‐1α as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC‐1α deficiency over inflammation and cell death in kidney injury. Kidney transcriptomic analyses of WT mice with folic acid‐induced AKI revealed 1398 up‐ and 1627 downregulated genes. Upstream transcriptional regulator analyses pointed to PGC‐1α as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC‐1α expression was shared by human kidney injury. Ppargc1a−/− mice had spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and increased Ngal expression. Upon AKI, Ppargc1a−/− mice had lower survival and more severe loss of renal function, tubular injury, and reduction in expression of mitochondrial PGC‐1α‐dependent genes in the kidney, and an earlier decrease in mitochondrial mass than WT mice. Additionally, surviving Ppargc1a−/− mice showed higher rates of tubular cell death, compensatory proliferation, expression of proinflammatory cytokines, NF‐κB activation, and interstitial inflammatory cell infiltration. Specifically, Ppargc1a−/− mice displayed increased M1 and decreased M2 responses and expression of the anti‐inflammatory cytokine IL‐10. In cultured renal tubular cells, PGC‐1α targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC‐1α inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC‐1α deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI.Sandra Zazo and Federico Rojo of the IIS‐FJD Biobank (B.0000647). FIS/Fondos FEDER (PI15/00298, CP14/00133, PI16/02057, PI16/01900, ISCIII‐RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD‐3686 CIFRA2‐CM. Grants from the Spanish ‘Ministerio de Economía Industria y Competitividad’ (MINEICO) and FEDER funds (Grant numbers SAF2015‐63904‐R, SAF2015‐71521‐REDC), and from the EC H2020 framework program Grant MSCA‐ITN‐2016‐721236 to MM. Salary support: ISCIII Miguel Servet and to ABS and MDS‐N. ISCIII Sara Borrell to JM‐MM, and Fundación Conchita Rabago to DMS. Consejería de Educación, Juventud y Deporte (Comunidad de Madrid/FSE) to MF‐B.Peer reviewe

La carga de enfermedad en España: resultados del Estudio de la Carga Global de las Enfermedades 2016

Background and objectives: The global burden of disease (GBD) project measures the health of populations worldwide on an annual basis, and results are available by country. We used the estimates of the GBD to summarise the state of health in Spain in 2016 and report trends in mortality and morbidity from 1990 to 2016. Material and methods: GBD 2016 estimated disease burden due to 333 diseases and injuries, and 84 risk factors. The GBD list of causes is hierarchical and includes 3 top level categories, namely: (1) communicable, maternal, neonatal, and nutritional diseases;(2) non-communicable diseases (NCDs), and (3)injuries. Mortality and disability-adjusted life-years (DALYs), risk factors, and progress towards the sustainable development goals (SDGs) are presented based on the GBD 2016 data in Spain. Results: There were 418,516 deaths in Spain in 2016, from a total population of 46.5 million, and 80.5% of them occurred in those aged 70 years and older. Overall, NCDs were the main cause of death: 388,617 (95% uncertainty interval 374,959–402,486), corresponding to 92.8% of all deaths. They were followed by 3.6% due to injuries with 15,052 (13,902–17,107) deaths, and 3.5% communicable diseases with 14,847 (13,208–16,482) deaths. The 5 leading specific causes of death were ischaemic heart disease (IHD, 14.6% of all deaths), Alzheimer disease and other dementias (13.6%), stroke (7.1%), chronic obstructive pulmonary disease (6.9%), and lung cancer (5.0%). Remarkable increases in mortality from 1990 to 2016 were observed in other cancers, lower respiratory infections, chronic kidney disease, and other cardiovascular disease, among others. On the contrary, road injuries moved down from 8th to 32nd position, and diabetes from 6th to 10th. Low back and neck pain became the number one cause of DALYs in Spain in 2016, just surpassing IHD, while Alzheimer disease moved from 9th to 3rd position. The greatest changes in DALYs were observed for road injuries dropping from 4th to 16th position, and congenital disorders from 17th to 35th; conversely, oral disorders rose from 25th to 17th. Overall, smoking is by far the most relevant risk factor in Spain, followed by high blood pressure, high body mass index, alcohol use, and high fasting plasma glucose. Finally, Spain scored 74.3 of 100 points in the SDG index classification in 2016, and the main national drivers of detrimental health in SDGs were alcohol consumption, smoking and child obesity. An increase to 80.3 points is projected in 2030. Conclusion: Low back and neck pain was the most important contributor of disability in Spain in 2016. There has seen a remarkable increase in the burden due to Alzheimer disease and other dementias. Tobacco remains the most important health issue to address in Spain.Antecedentes y objetivo: El estudio de la carga global de las enfermedades, conocido como GBD por sus siglas en inglés (global burden of disease), mide la salud poblacional en todo el mundo de forma anual y sus resultados están disponibles por país. Utilizamos las estimaciones GBD para resumir el estado de salud poblacional en España en 2016 y describir las tendencias en morbimortalidad de 1990 a 2016. Material y métodos: GBD 2016 estima la carga debida a 333 enfermedades y lesiones, y a 84 factores de riesgo. La lista de causas de GBD es jerárquica e incluye 3 categorías de nivel superior: 1) enfermedades transmisibles, maternas, neonatales y nutricionales; 2) enfermedades no transmisibles (ENT), y 3) accidentes. Se presentan la mortalidad, los años de vida ajustados por discapacidad (AVAD), los factores de riesgo y el progreso hacia los objetivos de desarrollo sostenible (ODS) a partir de los datos de GBD 2016 en España. Resultados: En 2016 en España hubo 418.516 muertes, de una población total de 46,5 millones, y el 80,5% de ellas ocurrieron en personas de 70 años o más. Las ENT fueron la principal causa de muerte (92,8%), con 388.617 (intervalo de incertidumbre del 95% 374.959–402.486), seguidas de los accidentes (3,6%), con 15.052 (13.902–17.107), y de las enfermedades transmisibles (3,5%), con 14.847 (13.208–16.482) muertes. Las 5 principales causas específicas de muerte fueron la cardiopatía isquémica (CI), con el 14,6% de todas las muertes, la enfermedad de Alzheimer y otras demencias (13,6%), el accidente cerebrovascular (7,1%), la enfermedad pulmonar obstructiva crónica (6,9%) y el cáncer de pulmón (5,0%). Se observaron incrementos notables en la mortalidad de 1990 a 2016 en otros cánceres, infecciones respiratorias del tracto inferior, enfermedad renal crónica y otras enfermedades cardiovasculares, entre otros. Por el contrario, los accidentes de tráfico bajaron del puesto 8 al 32 y la diabetes del 6 al 10. Los dolores de espalda y cervicales se convirtieron en la causa principal de AVAD en España en 2016, superando a la CI, mientras que la enfermedad de Alzheimer pasó del puesto 9 al 3. Los mayores cambios en AVAD se observaron para accidentes de tráfico, que cayeron de la posición 4 a la posición 16, y los trastornos congénitos, de la 17 a la 35; por el contrario, los trastornos orales aumentaron, pasando del puesto 25 al 17. En general, fumar es, con mucho, el factor de riesgo más relevante en España, seguido de presión arterial alta, índice de masa corporal alto, consumo de alcohol y glucemia alta en ayunas. Finalmente, España obtuvo 74,3 sobre 100 puntos en la clasificación del índice ODS en 2016, y los principales determinantes de salud nacionales relacionados con los ODS fueron el consumo de alcohol, el tabaquismo y la obesidad infantil. Se proyecta un aumento a 80,3 puntos en 2030. Conclusión: Los dolores de espalda y cervical fueron el contribuyente más importante de discapacidad en España en 2016. Hubo un aumento notable de la carga poblacional debida a la enfermedad de Alzheimer y otras demencias. El tabaco sigue siendo el riesgo para la salud más importante que debe abordarse en España

II Colombian Tromboemblism Venous Consensus

En el trombembolismo venoso (TEV), incluye la trombosis venosa profunda (TVP) y la embolia pulmonar (EP), como manifestaciones de una misma enfermedad. Constituye un fenómeno común con una incidencia de 300-600.000 casos de TVP y cerca de 50.000 muertes anuales causadas por EP, en Estados Unidos, y 10.000 muertes anuales, por la misma razón, en Francia.171-18