title: Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome.
abstract: Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated most of the metabolic disturbances. These findings are consistent with the hypothesis that inherited variation in the expression of Folr1 in the kidney influences the development of the metabolic syndrome and constitutes a previously unrecognized genetic mechanism that may contribute to increased risk for diabetes mellitus and cardiovascular disease.
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.). pravenec@biomed.cas.cz.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Jakub
authors.initials: J
authors.lastname: Krijt
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Jitka
authors.initials: J
authors.lastname: Sokolová
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Vladimír
authors.initials: V
authors.lastname: Landa
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Jan
authors.initials: J
authors.lastname: Šilhavý
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Miroslava
authors.initials: M
authors.lastname: Šimáková
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Škop
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Trnovská
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Kajiya
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P., V.Z., V.L., P.M., J.Š., M.Š.); Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic (V.K., J.K., J.Š.); Center of Experimental Medicine, Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.Š., J.T., L.K.); and Department of Laboratory Medicine, University of California, San Francisco (T.K., J.W., T.W.K.).
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Kurtz
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D058975:Folate Receptor 1 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D058975:Folate Receptor 1; D012313:RNA
keywords: blood pressure; cysteine; folate receptor 1; metabolic syndrome X; rats, inbred SHR