title: Neutrophil Gelatinase-Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids.
abstract: Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/mineralocorticoid receptor-mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by mineralocorticoid activation.
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Antoine
authors.initials: A
authors.lastname: Tarjus
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Ernesto
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Cristian
authors.initials: C
authors.lastname: Amador
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Céline
authors.initials: C
authors.lastname: Latouche
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Renaud
authors.initials: R
authors.lastname: Fay
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.).
authors.forename: Natalia
authors.initials: N
authors.lastname: López-Andrés
authors.affiliation: From the INSERM UMR 1138 Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (A.T., C.A., C.L., S.E.M., N.F., F.J.); NAVARRABIOMED-FUNDACIÓN MIGUEL SERVET, Pamplona, Spain (E.M.-M., N.L.-A.); The Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON, Canada (T.B., T.W.M.); INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); Université de Lorraine, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.); and INI-CRCT F-CRIN, Nancy, France (R.F., P.R., F.Z., N.L.-A., F.J.). frederic.jaisser@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000450:Aldosterone / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000139:chemically induced / Q000503:physiopathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005355:Fibrosis; D037502:Galectin 3 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D006984:Hypertrophy; D007668:Kidney / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009392:Nephrectomy / Q000009:adverse effects; D056128:Obesity, Abdominal / Q000097:blood / Q000503:physiopathology*; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000209:Acute-Phase Proteins; D016207:Cytokines; D037502:Galectin 3; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011347:Procollagen; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C047202:procollagen Type I N-terminal peptide; C041876:procollagen Type III-N-terminal peptide; C071332:Lcn2 protein, mouse; D000450:Aldosterone; C092073:cardiotrophin 1
keywords: aldosterone; collagen type I; fibroblast; lipocalin 2; mineralocorticoid receptor