Molecular pathophysiology of fibrosis

Research summary:

Our laboratory is interested in the molecular mechanisms leading to fibrogenesis in human pathology. Organ fibrosis is a final common outcome for many diseases such as diabetic nephropathy, liver cirrhosis, scleroderma or myocardial sclerosis. It involves the replacement of cellular living tissue by extracellular matrix, with the subsequent functional derangement. Thus, it is crucial to understand the underlying molecular pathways leading to fibrosis development. MicroRNAs are essential posttranscriptional regulators of gene expression for multiple physiological and pathophysiological pathways, including fibrosis. Kidney fibrosis is the ultimate cause of chronic kidney disease, where mitochondrial function and bioenergetics failure are key features. During the past two years we have focused on renal fibrosis regarding two questions: a) the role of oxidative metabolism in the genesis of renal injury and repair and b) the role of miRNAs involved in specific metabolic pathways critical for tubular epithelial cell function. We aim to prevent, defer or revert fibrosis in the kidney by understanding underlying metabolic changes and eventually by halting the bioenergetics havoc associated to kidney fibrosis. To this end we use animal models with specific gain-of-function for critical enzymes involved in oxidative metabolism as well as animals with a disruption of the circadian rhythm. These studies are complemented by cellular models and biochemical approaches directed towards the study of mitochondrial biogenesis and function.

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Figure 1. Microphotographs of Sirius Red staining from kidney sections showing protection from fibrosis in mice treated with miR-9-5p in the unilateral ureteral obstruction (UUO) renal injury model.

*  Associate editor of the Redox Biology magazine  http://www.journals.elsevier.com/redox-biology/

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* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Fernádez HernándezLaura1034456Estudiante TFG
Herrero LahuertaJosé Ignacio1034456jiherrero(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Lamas PeláezSantiago1034455slamas(at)cbm.csic.esE. Profesores de Investigación de Organismos Públicos de Investigación
Miguel HerranzVerónica1034456vmiguel(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Ranz FernándezIrene1034456Estudiante TFG
Rey SerraCarlos1034456carlos.rey(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Sirera ConcaBelén1034456Estudiante TFM
Tituaña FajardoJessica Paola1034456jtituana(at)cbm.csic.esTitulado Medio de Actividades Tecn.y Prof.GP2

Relevant publications:

  • Ruiz-Ortega M, Rayego-Mateos S, Lamas S, Ortiz A, Rodrigues-Díez R. Targeting the progression of chronic kidney disease. Nature Reviews Nephrology. 2020, DOI: 10.1038/s41581-019-0248-y
  • Fierro-Fernández M, Miguel V, Márquez-Expósito L, Nuevo-Tapioles C, Herrero JI, Blanco-Ruiz E, Tituaña J, Castillo C, Cannata P, Monsalve M, Ruiz-Ortega M, Ramos R, Lamas S. MiR-9-5p protects from kidney fibrosis by metabolic reprogramming.FASEB Journal. 2020. 34(1):410-431.
  • Price NL*, Miguel V*, Ding W, Singh AK, Malik S, Rotllan N, Moshnikova A, Toczek J, Zeiss C, Sadeghi M, Arias Rueda N, Baldán A, Andreev O, Rodriguez-Puyol D, Bahal R, Reshetnyak YK, Suárez Y, Fernández-Hernando C*, Lamas S*. Genetic deficiency and pharmacological inhibition of miR-33 enhances renal fatty acid oxidation and attenuates kidney fibrosis. JCI Insight.2019. 4 (22).
  • Miguel V, Lamas S. Redox Distress in Organ Fibrosis: The Role of Non-Coding RNAs. Oxidative Stress: Eustress and Distress. Role in Health and Disease Processes. Helmut Sies (Ed.). Elsevier. pp 779-820. 2019
  • Espinosa-Díez C, Miguel V, Vallejo S, Sánchez FJ, Sandoval E, Blanco E, Cannata P, Peiró C, Sánchez-Ferrer CF, Lamas S. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol. 2018. 14:88-99.
  • Miguel V, Busnadiego O, Fierro-Fernandez M, Lamas S. Protective role of miR-9-5p in the fibrogenic transformation of human dermal fibroblasts. Fibrogenesis and Tissue Repair. 9:7, 2016.
  • Sánchez-Gómez FJ, Calvo E, Bretón-Romero R, Fierro-Fernández M, Anilkumar N, Shah AM, Schröder K, Brandes RP, Vázquez J, Lamas S. NOX4-dependent hydrogen peroxide promotes shear stress-induced SHP2 sulfenylation and eNOS activation. Free Radic Biol Med. 89:419-30, 2015.
  • Fierro-Fernández M, Busnadiego Ó, Sandoval P, Espinosa-Díez C, Blanco-Ruiz E, Rodríguez M, Pian H, Ramos R, López-Cabrera M, García-Bermejo ML, Lamas S. miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2. EMBO Rep.16:1358-77, 2015.
  • Espinosa-Diez C, Fierro-Fernández M, Sánchez-Gómez F, Rodríguez-Pascual F, Alique M, Ruiz-Ortega M, Beraza N, Martínez-Chantar ML, Fernández-Hernando C, Lamas S. Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-β-Dependent Fibrogenesis. Antioxid Redox Signal. 23:1092-1105, 2015.

Doctoral theses: 

  • Veronica Miguel.(2019). The Metabolic Basis  of Renal Fibrosis: Role of microRNAs and insight from genetic models targeting lipid metabolism. Director: Santiago Lamas.
  • M. Cristina  Espinosa Diez (2015). Papel de la g-glutamilcistein ligasa en modelos de daño vascular y fibrótico e implicación de miR-433 en la sintesis de  glutation. Director: Santiago Lamas
  • M. Ángeles Higueras López (2014). Fisiología y Fisiopatología de DLK-1 en el Endotelio Vascular. Universidad Complutense de Madrid. Directores: Santiago Lamas y Patricia Rodríguez
  • Rosa Bretón Romero (2013). Redox Signaling Responses to Laminar Shear Stress in vascular endothelial cells. Universidad Autónoma de Madrid. Director:Santiago Lamas
  • David Lagares Salto (2012) Implicaciones Fisiopatológicas y Terapeuticas del eje TGF-beta/ET-1 y la Quinasa de Adhesión Focal en los procesos Fibróticos. Universidad Autónoma de Madrid. Directores: Santiago Lamas Peláez y Fernando Rodríguez Pascual.

Patents:

  • European Application "Compounds for prevention and/or treatment of fibrotic diseases" Application No/Patent No 14382239.3-1401
  • International application  201031547 “Uso de Dlk1 como inhibidor de angiogénesis”, Dec 2011.

Organización de actividades I + D:

  • Workshop "Redox Biology as a major drive to the undestandidng of pathophysiology : Contibutions from the CONSOLREDOX network". Salamanca. Abril 2018
  • "Redox signaling and oxidative stress in health and disease IV Spanish and Portuguese meeting on free radicals" Valencia. Junio 2012
  • "Workshop on Gasotransmitters in health and disease" Madrid. Enero 2012
  • "XVII Simposio Internacional del Instituto "Reina Sofía" de Investigaciones Nefrológicas". Noviembre 2011
  • "Current Trends In Biomedicine. Molecular and Cellular Bases of Redox Signaling and Oxidative Stress: Implications in Biomedicine". Universidad Internacional de Andalucía. Simposium Internacional Baeza. Noviembre 2011
  • Curso de Verano "La fibrosis tisular en la enfermedad humana". Fundación General de la Universidad de Álcala de Henares. Septiembre 2012.

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