Loss of NLRP6 increases the severity of kidney fibrosis

While NLRP3 contributes to kidney fibrosis, the function of most NOD‐likereceptors (NLRs) in chronic kidney disease (CKD) remains unexplored. Toidentify further NLR members involved in the pathogenesis of CKD, wesearched for NLR genes expressed by normal kidneys and differentiallyexpressed in human CKD transcriptomics databases. For NLRP6, lower kidneyexpression correlated with decreasing glomerular filtration rate. The role andmolecular mechanisms of Nlrp6 in kidney fibrosis were explored in wild‐typeand Nlrp6‐deficient mice and cell cultures. Data mining of single‐celltranscriptomics databases identified proximal tubular cells as the main site ofNlrp6 expression in normal human kidneys and tubular cell Nlrp6 was lost inCKD. We confirmed kidney Nlrp6 downregulation following murine unilateralureteral obstruction. Nlrp6‐deficient mice had higher kidney p38 MAPKactivation and more severe kidney inflammation and fibrosis. Similar resultswere obtained in adenine‐induced kidney fibrosis. Mechanistically, profibroticcytokines transforming growth factor beta 1 (TGF‐β1) and TWEAK decreasedNlrp6 expression in cultured tubular cells, and Nlrp6 downregulation resulted inincreased TGF‐β1 and CTGF expression through p38 MAPK activation, as wellas in downregulation of the antifibrotic factor Klotho, suggesting that loss ofNlrp6 promotes maladaptive tubular cell responses. The pattern of geneexpression following Nlrp6 targeting in cultured proximal tubular cells wasconsistent with maladaptive transitions for proximal tubular cells described insingle‐cell transcriptomics datasets. In conclusion, endogenous constitutiveNlrp6 dampens sterile kidney inflammation and fibrosis. Loss of Nlrp6expression by tubular cells may contribute to CKD progressionSociedad Española de Nefrología, Comunidad de Madrid en Biomedicina P2022/BMD‐7223, CIFRA_COR‐CM and COST Action PERMEDIK CA21165, supported by COST(European Cooperation in Science and Technology). MDSN and ABS were supportedby MICINN Ramon y Cajal program RYC2018‐024461‐I and RYC2019‐026916‐Irespectively. IIS‐Fundación Jimenez Diaz Biobank, part of the Spanish Biobanks Platform (PT17/0015/0006); MICINN; This work was supported by Instituto de Salud Carlos III (ISCIII)‐FIS/Fondo Europeo de Desarrollo Regional FEDER grants (PI18/01366, PI21/00251, PI22/00050, PI22/00469), Ministerio de Ciencia e Innovación y Agencia Estatal de Investigación/Next Generation EU (CNS2022‐135937), ERA‐PerMed‐JTC2022 (SPAREKID AC22/00027), RICORS program to RICORS2040 (RD21/0005/0001) funded by European Union–Next Generation EU, Mecanismo para la Recuperación y la Resiliencia (MRR) and SPACKDc PMP21/00109 FEDE

Incisión fluvial a partir del conjunto multinivel de cuevas de La Galiana (Parque natural del río Lobos, Soria)

El conjunto endokárstico de La Galiana (Cañón del río Lobos, Cordillera Ibérica, provincia de Soria) está formado por tres niveles de galerías horizontales (La Galiana Alta, La Galiana Baja y Cueva del Lago) localizadas a 1099, 966 y 953 m s.n.m. respectivamente. Representan niveles de estabilización de la superficie freática y su nivel de base fluvial. El contexto geomorfológico y los datos paleomagnéticos indican que coladas estalagmítica de La Galiana Alta son anteriores a los 3,596 Ma. Por otro lado, la edad U/Th más antigua obtenida en espeleotemas de La Galiana Baja es de 224 ka. Las diferencias altimétricas entre galerías (133 y 13 m) y edades obtenida permiten calcular tasas máximas de encajamiento fluvial entre 39 y 58 mm/ka

Fluvial incision from La Galiana multilevel cave system (Río Lobos Natural Park, Soria, Spain)

El conjunto endokárstico de La Galiana (Cañón del río Lobos, Cordillera Ibérica, provincia de Soria) está formado por tres niveles de galerías horizontales (La Galiana Alta, La Galiana Baja y Cueva del Lago) localizadas a 1099, 966 y 953 m s.n.m. respectivamente. Representan niveles de estabilización de la superficie freática y su nivel de base fluvial. El contexto geomorfológico y los datos paleomagnéticos indican que coladas estalagmíticas de La Galiana Alta son anteriores a los 3,596 Ma. Por otro lado, la edad U/Th más antigua obtenida en espeleotemas de La Galiana Baja es de 224 ka. Las diferencias altimétricas entre galerías (133 y 13 m) y edades obtenidas permiten calcular tasas máximas de encajamiento fluvial entre 39 y 58 mm/kaLa Galiana endokarstic system (Cañón del río Lobos, Iberian Ranges, Soria province) is constituted by three staircase horizontal galleries (La Galiana Alta, La Galiana Baja and the Cueva del Lago) located at 1099, 966 and 953 m a.s.l. respectively. These three levels correspond to distinct stages of stabilized water-table linked to local fluvial evolution of their base levels. Geomorphic context and palaeomagnetic data display that flowstones in La Galiana Alta are older than 3.596 Ma. The oldest U-series age obtained in speleothems from La Galiana Baja gallery is ca. 224 ka.Altitude differences between galleries (133 and 13 m, respectively) and obtained ages allow us to calculate maximum fluvial incision rates between 39 and 58 mm/ka

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3This work was mainly supported by projects from the Instituto de Salud Carlos III (ISCIII) (PI20/00763, PI20/01482, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, IFEQ21/00012, PI19/00588, PI22/00469) and co-funded by the European Union, Ministerio de Universidades (FPU20/03005), Ministerio de Ciencia e Innovaci on (RYR2019-026916-I), the Education and Research Council of Madrid (PEJ-2021- AI/SAL-21426), Biomedicine Network Comunidad de Madrid (P2022/BMD-7223 CIFRA_COR-CM), Spanish Network in Inflammasoma and Pyroptosis in Chronic Disease and Cancer (RED2022-134511-T), and the Spanish Society of Nephrology SEN/SENEFRO Foundatio

Tweak, un nuevo mediador del daño renal: modulación terapéutica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Bioquímica. Fecha de lectura: 21 de Noviembre de 200

TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome

There is a complex relationship between cardiac and renal disease, often referred to as the cardiorenal syndrome. Heart failure adversely affects kidney function, and both acute and chronic kidney disease are associated with structural and functional changes to the myocardium. The pathological mechanisms and contributing interactions that surround this relationship remain poorly understood, limiting the opportunities for therapeutic intervention. The cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed in injured kidneys and heart. The TWEAK-Fn14 axis promotes responses that drive tissue injury such as inflammation, proliferation, fibrosis and apoptosis, while restraining the expression of tissue protective factors such as the anti-aging factor Klotho and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivador-1α (PGC-1α). High levels of TWEAK induce cardiac remodeling, and promote inflammation, tubular and podocyte injury and death, fibroblast proliferation and, ultimately, renal fibrosis. Accordingly, targeting the TWEAK-Fn14 axis is protective in experimental kidney and heart disease. TWEAK has also emerged as a biomarker of kidney damage and cardiovascular outcomes and has been successfully targeted in clinical trials. In this review, we update our current knowledge of the roles of the TWEAK-Fn14 axis in cardiovascular and kidney disease and its potential contribution to the cardiorenal syndrome. This article is protected by copyright. All rights reserved.Sin financiación7.996 JCR (2020) Q1, 38/242 Oncology2.964 SJR (2020) Q1, 6/206 Pathology and Forensic MedicineNo data IDR 2020UE

Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected conditions, and CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches are needed. Mitochondrial dysfunction and oxidative stress have emerged as drivers of kidney injury in acute and chronic settings, promoting the AKI-to-CKD transition. In this work, we review the role of mitochondrial dysfunction and oxidative stress in AKI and CKD progression and discuss novel therapeutic approaches. Specifically, evidence for mitochondrial dysfunction in diverse models of AKI (nephrotoxicity, cytokine storm, and ischemia-reperfusion injury) and CKD (diabetic kidney disease, glomerulopathies) is discussed; the clinical implications of novel information on the key role of mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), and carnitine palmitoyl-transferase 1A (CPT1A) in kidney disease are addressed; the current status of the clinical development of therapeutic approaches targeting mitochondria are updated; and barriers to the clinical development of mitochondria-targeted interventions are discussed, including the lack of clinical diagnostic tests that allow us to categorize the baseline renal mitochondrial dysfunction/mitochondrial oxidative stress and to monitor its response to therapeutic intervention. Finally, key milestones for further research are proposedFIS/Fondos FEDER (PI18/01366, PI19/00588, PI19/00815, DTS18/00032, PI21/00251, PI20/000140 ERA-PerMed-JTC2018 KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, SPACKDc PMP21/00109, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM; Instituto de Salud Carlos III (ISCIII) RICORS2040 (RD21/0005/0001), Financiado por la Unión Europea—NextGenerationEU and Mecanismo para la Recuperación y la Resiliencia (MRR) and Salary support: AC18/00064 to M.F.-B., ISCIII PFIS to A.M.L.-D., Ramon y Cajal program to A.B.S. and M.D.S.N., MICIU to J.G.-M., FEBS Long-Term Fellowship to V.

Dinámica glacial, clima y vegetación en el Parque Nacional de Ordesa y Monte Perdido durante el Holoceno

[EN] New and more detailed geomorphological, hydrological, vegetational and climatic reconstructions for the Holocene in the PNOMP have been obtained from the pluridisciplinary study of three records (La Larri, La Estiva and Marboré). La Larri paleolake was originated when the Pineta glacier blocked the valley before 35 ka and existed till 11 ka when it was drained when the glacier receded. Marboré Lake record spans the last 11 kyrs. Facies, geochemistry and magnetic properties identify a large glacier influence between 11 and 9.2 ka. The 9.2- 4.1 ka was relatively more humid. The Mid Holocene transition ca 5 – 4.5 ka to more arid conditions was detected in both Marboré and La Estiva. During the last 3 millennia several arid phases occurred (end of the Roman Period, the High Middle Ages, the Medieval Climate Anomaly). The LIA is characterized by higher runoff and colder climate. However, pollen studies indicate a higher human pressure in the mountains during this period. Both, historic global atmospheric contamination and local influx of the mining activities in the Alto Cinca valley are detected in the Marboré record. The Marboré and Monte Perdido glaciers have been receding during the last centuries, with several moraines ascribed to the first phase of the LIA, and a large expansion during the early XXth century. The main factors controlling recent glacier retreat are the increase in maximum summer temperatures and the decrease in snow precipitation in winter.Proyecto financiado por el Organismo Autónomo Parques Nacionales Dinámica glacial, clima y vegetación en el Parque Nacional de Ordesa - Monte Perdido durante el Holoceno (ref: 83/2009). Agradecemos a todo el personal del PNOMP su apoyo para la realización de los trabajos de campo.Peer Reviewe