Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney
Verónica Miguel,
Carlos Rey-Serra,
Jessica Tituaña,
Belén Sirera,
Elena Alcalde-Estévez,
J. Ignacio Herrero,
Irene Ranz,
Laura Fernández,
Carolina Castillo,
Lucía Sevilla,
James Nagai,
Katharina C. Reimer,
Jitske Jansen,
Rafael Kramann,
Ivan G. Costa,
Ana Castro,
David Sancho,
José Miguel Rodríguez González-Moro,
Santiago Lamas
Affiliations
Verónica Miguel
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029, Madrid, Spain; Corresponding author. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029, Madrid, Spain.
Carlos Rey-Serra
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Jessica Tituaña
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Belén Sirera
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Elena Alcalde-Estévez
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
J. Ignacio Herrero
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Irene Ranz
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Laura Fernández
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain
Carolina Castillo
Department of Pathology. University Hospital ''Príncipe de Asturias'', Alcalá de Henares, Madrid, Spain
Lucía Sevilla
Department of Pneumology, University Hospital “Principe de Asturias”, Alcala de Henares, Madrid, Spain
James Nagai
Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
Katharina C. Reimer
Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany; Institute for Biomedical Technologies, Department of Cell Biology, RWTH Aachen University, Aachen, Germany
Jitske Jansen
Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany; Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
Rafael Kramann
Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany
Ivan G. Costa
Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
Ana Castro
Instituto de Química Medica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid, Spain
David Sancho
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029, Madrid, Spain
José Miguel Rodríguez González-Moro
Department of Pneumology, University Hospital “Principe de Asturias”, Alcala de Henares, Madrid, Spain
Santiago Lamas
Program of Physiological and Pathological Processes, Centro de Biología Molecular ''Severo Ochoa'' (CBMSO) (CSIC-UAM), Madrid, Spain; Corresponding author. Centro de Biología Molecular Severo Ochoa, Calle Nicolás Cabrera 1, Madrid, 28049, Spain.
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.
