Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the kidneys

Spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHRSP) are frequently used as models not only of essential hypertension and stroke, but also of attention-deficit hyperactivity disorder (ADHD). Normotensive Wistar-Kyoto (WKY) rats are normally used as controls in these studies. In the present study, we aimed to identify the genes causing hypertension and stroke, as well as the genes involved in ADHD using these rats. We previously analyzed gene expression profiles in the adrenal glands and brain. Since the kidneys can directly influence the functions of the cardiovascular, endocrine and sympathetic nervous systems, gene expression profiles in the kidneys of the 3 rat strains were examined using genome-wide microarray technology when the rats were 3 and 6 weeks old, a period in which rats are considered to be in a pre-hypertensive state. Gene expression profiles were compared between the SHRs and WKY rats and also between the SHRSP and SHRs. A total of 232 unique genes showing more than a 4-fold increase or less than a 4-fold decrease in expression were isolated as SHR- and SHRSP-specific genes. Candidate genes were then selected using two different web tools: the 1st tool was the Database for Annotation, Visualization and Integrated Discovery (DAVID), which was used to search for significantly enriched genes and categorized them using Gene Ontology (GO) terms, and the 2nd was Ingenuity Pathway Analysis (IPA), which was used to search for interactions among SHR- and also SHRSP-specific genes. The analyses of SHR-specific genes using IPA revealed that B-cell CLL/lymphoma 6 (Bcl6) and SRY (sex determining region Y)-box 2 (Sox2) were possible candidate genes responsible for causing hypertension in SHRs. Similar analyses of SHRSP-specific genes revealed that angiotensinogen (Agt), angiotensin II receptor-associated protein (Agtrap) and apolipoprotein H (Apoh) were possible candidate genes responsible for triggering strokes. Since our results revealed that SHRSP-specific genes isolated from the kidneys of rats at 6 weeks of age, included 6 genes related to Huntington's disease, we discussed the genetic association between ADHD and Huntington's disease.

[1]  T. Partonen,et al.  CREM mutations and ADHD symptoms. , 2009, Medical hypotheses.

[2]  C. Férec,et al.  Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis , 2001, Clinical genetics.

[3]  E. Thomas,et al.  Striatal specificity of gene expression dysregulation in Huntington's disease , 2006, Journal of neuroscience research.

[4]  Limin Liu,et al.  Disruption of the Lecithin:Retinol Acyltransferase Gene Makes Mice More Susceptible to Vitamin A Deficiency* , 2005, Journal of Biological Chemistry.

[5]  S. Chattopadhyay,et al.  Coordinated regulation of p53 apoptotic targets BAX and PUMA by SMAR1 through an identical MAR element , 2010, The EMBO journal.

[6]  D. Viggiano,et al.  Involvement of Norepinephrine in the Control of Activity and Attentive Processes in Animal Models of Attention Deficit Hyperactivity Disorder , 2004, Neural plasticity.

[7]  M. Schmid,et al.  Colocalization and heteromerization between the two human oncogene POZ/zinc finger proteins, LAZ3 (BCL6) and PLZF , 2000, Oncogene.

[8]  J. Harney,et al.  Activation of thyroid hormone is transcriptionally regulated by epidermal growth factor in human placenta-derived JEG3 cells. , 2008, Endocrinology.

[9]  A. Schroit,et al.  Plasmin-cleaved beta-2-glycoprotein 1 is an inhibitor of angiogenesis. , 2007, The American journal of pathology.

[10]  E. Woodcock,et al.  UTP Transactivates Epidermal Growth Factor Receptors and Promotes Cardiomyocyte Hypertrophy Despite Inhibiting Transcription of the Hypertrophic Marker Gene, Atrial Natriuretic Peptide* , 2004, Journal of Biological Chemistry.

[11]  Sarah J Tabrizi,et al.  Gene expression in Huntington's disease skeletal muscle: a potential biomarker. , 2005, Human molecular genetics.

[12]  Michael L. Atchison,et al.  PU.1 Can Recruit BCL6 to DNA To Repress Gene Expression in Germinal Center B Cells , 2009, Molecular and Cellular Biology.

[13]  A. Schroit,et al.  Plasmin-Cleaved β-2-Glycoprotein 1 Is an Inhibitor of Angiogenesis , 2007 .

[14]  D. Townsend,et al.  “Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System , 2006, Molecular and Cellular Biology.

[15]  Mehdi Farshbaf,et al.  Rodent Models of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[16]  B. Spencer‐Dene,et al.  c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling , 2012, The Journal of cell biology.

[17]  F. He,et al.  Protein interaction data set highlighted with human Ras-MAPK/PI3K signaling pathways. , 2008, Journal of proteome research.

[18]  Gideon Rechavi,et al.  Identification of Direct p73 Target Genes Combining DNA Microarray and Chromatin Immunoprecipitation Analyses* , 2002, The Journal of Biological Chemistry.

[19]  J. Blangero,et al.  A transcriptional profile of the decidua in preeclampsia. , 2011, American journal of obstetrics and gynecology.

[20]  D. Denhardt,et al.  Osteopontin: role in immune regulation and stress responses. , 2011, Cytokine & growth factor reviews.

[21]  Masamichi Ishizaka,et al.  In vitro selection of Jun-associated proteins using mRNA display. , 2004, Nucleic acids research.

[22]  B. Hollis,et al.  Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. , 2008, Endocrinology.

[23]  S. Umemura,et al.  Novel Regulatory Effect of Angiotensin II Type 1 Receptor–Interacting Molecule on Vascular Smooth Muscle Cells , 2007, Hypertension.

[24]  P. Hopkins,et al.  Ala92 Type 2 Deiodinase Allele Increases Risk for the Development of Hypertension , 2007, Hypertension.

[25]  V. de Waard,et al.  Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis , 2011, The Journal of experimental medicine.

[26]  A. Guyton,et al.  Abnormal Renal Function and Autoregulation in Essential Hypertension , 1991, Hypertension.

[27]  Nicholas J Schork,et al.  Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension. , 2005, American journal of hypertension.

[28]  L. Luttrell,et al.  Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells. , 2012, Molecular endocrinology.

[29]  V. Reghunandanan,et al.  Neurotransmitters of the suprachiasmatic nuclei , 2006, Journal of circadian rhythms.

[30]  J. Fletcher,et al.  Adrenomedullary function during cognitive testing in attention-deficit/hyperactivity disorder. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[31]  M. Simon,et al.  SPI-B Activates Transcription via a Unique Proline, Serine, and Threonine Domain and Exhibits DNA Binding Affinity Differences from PU.1* , 1999, The Journal of Biological Chemistry.

[32]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[33]  A. Dominiczak,et al.  Genetics of hypertension: From experimental animals to humans , 2010, Biochimica et biophysica acta.

[34]  D. Denhardt,et al.  Osteopontin: a protein with diverse functions , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  J. Olson,et al.  Regional and cellular gene expression changes in human Huntington's disease brain. , 2006, Human molecular genetics.

[36]  Albert B. Reynolds,et al.  The Catenin p120ctnInteracts with Kaiso, a Novel BTB/POZ Domain Zinc Finger Transcription Factor , 1999, Molecular and Cellular Biology.

[37]  R. D. De Lisle,et al.  Inflammation of the cystic fibrosis mouse small intestine. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[38]  M. Washburn,et al.  The SOX2-Interactome in Brain Cancer Cells Identifies the Requirement of MSI2 and USP9X for the Growth of Brain Tumor Cells , 2013, PloS one.

[39]  L. Navar,et al.  The absence of intrarenal ACE protects against hypertension. , 2013, The Journal of clinical investigation.

[40]  M. Minami,et al.  Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder , 2002, Behavioural pharmacology.

[41]  K. Shimada,et al.  Gene expression in the adrenal glands of three spontaneously hypertensive rat substrains. , 2010, Molecular medicine reports.

[42]  P. Soubrié,et al.  Altered neurotensin mrna expression in mice lacking the dopamine transporter , 2004, Neuroscience.

[43]  A. Sabichi,et al.  Identification of cJun-responsive genes in Rat-1a cells using multiple techniques: increased expression of stathmin is necessary for cJun-mediated anchorage-independent growth , 2003, Oncogene.

[44]  R. D. Rudic,et al.  Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. , 2009, The American journal of pathology.

[45]  H. Drexler,et al.  The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. , 2006, Circulation research.

[46]  H. Okamura,et al.  Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: gene expression profiles in the brain. , 2014, International journal of molecular medicine.

[47]  Guosong Qiu,et al.  Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages Published, JLR Papers in Press, July 20, 2007. , 2007, Journal of Lipid Research.

[48]  Alexander L. Dent,et al.  Repression of AP-1 Function: A Mechanism for the Regulation of Blimp-1 Expression and B Lymphocyte Differentiation by the B Cell Lymphoma-6 Protooncogene1 , 2002, The Journal of Immunology.

[49]  D. Ambrosetti,et al.  Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation , 2005, The Journal of cell biology.

[50]  J. Chiang,et al.  Cytokine regulation of human sterol 12alpha-hydroxylase (CYP8B1) gene. , 2005, American Journal of Physiology - Gastrointestinal and Liver Physiology.

[51]  H. Nevanlinna,et al.  Mutations N34S and P55S of the SPINK1 gene in patients with chronic pancreatitis or pancreatic cancer and in healthy subjects: A report from Finland , 2005, Scandinavian journal of gastroenterology.

[52]  K. Sabapathy,et al.  c-Jun Regulates the Stability and Activity of the p53 Homologue, p73* , 2004, Journal of Biological Chemistry.

[53]  K. Okamoto,et al.  Development of a strain of spontaneously hypertensive rats. , 1963, Japanese circulation journal.

[54]  L. Cai,et al.  Angiotensin II-induced p53-dependent cardiac apoptotic cell death: its prevention by metallothionein. , 2009, Toxicology letters.

[55]  L. Zitvogel,et al.  Decoding Cell Death Signals in Inflammation and Immunity , 2010, Cell.

[56]  J. Cristol,et al.  Simvastatin Prevents Angiotensin II–Induced Cardiac Alteration and Oxidative Stress , 2002, Hypertension.

[57]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[58]  S. Nishiguchi,et al.  Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats. , 2013, International journal of molecular medicine.

[59]  J. Chiang,et al.  Cytokine regulation of human sterol 12α-hydroxylase (CYP8B1) gene , 2005 .

[60]  D. Housman,et al.  The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  G. Kay,et al.  Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. , 2000, Circulation research.

[62]  T R Butt,et al.  Retinoid X receptor isotype identity directs human vitamin D receptor heterodimer transactivation from the 24-hydroxylase vitamin D response elements in yeast. , 1996, Molecular endocrinology.

[63]  P. D. de Jong,et al.  Targeted Disruption of the Idol Gene Alters Cellular Regulation of the Low-Density Lipoprotein Receptor by Sterols and Liver X Receptor Agonists , 2011, Molecular and Cellular Biology.

[64]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[65]  R. Roberts,et al.  A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy , 2003, The EMBO journal.

[66]  K. Tomita,et al.  Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain , 2001, The EMBO journal.

[67]  A. Dominiczak,et al.  Functional genomics in rodent models of hypertension , 2004, The Journal of physiology.

[68]  R. Maldonado,et al.  Altered emotional and locomotor responses in mice deficient in the transcription factor CREM. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Yi Fu,et al.  Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo , 2007, Proceedings of the National Academy of Sciences.

[70]  T. Nabika,et al.  The Stroke-Prone Spontaneously Hypertensive Rat: How Good Is It as a Model for Cerebrovascular Diseases? , 2004, Cellular and Molecular Neurobiology.

[71]  Godfrey L. Smith,et al.  Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts. , 2013, American journal of physiology. Heart and circulatory physiology.

[72]  K. Takeda,et al.  Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone , 2003, Hypertension.

[73]  E. Wagner,et al.  Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation , 2000, Nature Genetics.

[74]  M. Piascik,et al.  The α1D-Adrenergic Receptor Induces Vascular Smooth Muscle Apoptosis via a p53-Dependent Mechanism , 2008, Molecular Pharmacology.

[75]  S. De Flora,et al.  Gene Expression in the Lung of p53 Mutant Mice Exposed to Cigarette Smoke , 2004, Cancer Research.

[76]  K. Okamoto.  Establishment of the strokeprone spontaneously hypertensive rat (SHR) , 1972 .

[77]  A. Nagaoka,et al.  Pathogenesis and prevention of stroke in spontaneously hypertensive rats. , 1975, Clinical science and molecular medicine. Supplement.

[78]  B. Nilsson,et al.  Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein , 2009, Molecular Cancer Research.

[79]  S. Faraone,et al.  Molecular genetics of attention deficit hyperactivity disorder. , 2010, The Psychiatric clinics of North America.

[80]  K. Elenitoba-Johnson,et al.  Analysis of BCL6-interacting Proteins by Tandem Mass Spectrometry*S , 2005, Molecular & Cellular Proteomics.

[81]  J. Witztum,et al.  The role of innate immunity in atherogenesis11 Guest editor for this article was Linda Curtiss, the Scripps Research Institute. Published, JLR Papers in Press, December 22, 2008. , 2009, Journal of Lipid Research.

[82]  J. Zavadil,et al.  Distinct Functions of Sox2 Control Self-Renewal and Differentiation in the Osteoblast Lineage , 2011, Molecular and Cellular Biology.