1 3295 119 HIGH PHOSPHATE-INDUCED DOWNREGULATION OF PPARGAMMA CONTRIBUTES TO CKD-ASSOCIATED VASCULAR CALCIFICATION. MEDIAL ARTERIAL CALCIFICATION ASSOCIATED WITH HYPERPHOSPHATEMIA IS A MAIN CAUSE OF CARDIOVASCULAR MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), BUT THE MECHANISMS UNDERLYING HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION REMAIN LARGELY UNKNOWN. HERE, WE OBSERVED A SIGNIFICANT DECREASE IN THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) IN CALCIFIED ARTERIES BOTH IN CKD PATIENTS AND IN A MOUSE MODEL OF CKD WITH HYPERPHOSPHATEMIA. IN VITRO, HIGH PHOSPHATE TREATMENT LED TO A DECREASED EXPRESSION OF PPARGAMMA IN MOUSE VASCULAR SMOOTH MUSCLE CELLS (VMSCS), ACCOMPANIED BY APPARENT OSTEOGENIC DIFFERENTIATION AND CALCIFICATION. PRETREATMENT WITH PPARGAMMA AGONIST ROSIGLITAZONE SIGNIFICANTLY REVERSED HIGH PHOSPHATE-INDUCED VSMCS CALCIFICATION. FURTHER INVESTIGATION SHOWED THAT METHYL-CPG BINDING PROTEIN 2 (MECP2)-MEDIATED EPIGENETIC REPRESSION WAS INVOLVED IN HIGH PHOSPHATE-INDUCED PPARGAMMA DOWNREGULATION. MOREOVER, THE EXPRESSION OF KLOTHO THAT HAS THE ABILITY TO INHIBIT VASCULAR CALCIFICATION BY REGULATING PHOSPHATE UPTAKE DECREASED WITH THE PPARGAMMA REDUCTION IN VSMCS AFTER HIGH PHOSPHATE TREATMENT, AND ROSIGLITAZONE FAILED TO INHIBIT HIGH PHOSPHATE-INDUCED CALCIFICATION IN VSMCS WITH KNOCKDOWN OF KLOTHO OR IN AORTIC RINGS FROM KLOTHO-DEFICIENT (KL/KL) MICE. FINALLY, AN IN VIVO STUDY DEMONSTRATED THAT ORAL ADMINISTRATION OF ROSIGLITAZONE COULD INCREASE KLOTHO EXPRESSION AND PROTECT AGAINST HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION IN CKD MICE. THESE FINDINGS SUGGEST THAT THE INHIBITION OF PPARGAMMA EXPRESSION MAY CONTRIBUTE TO THE PATHOGENESIS OF HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION, WHICH MAY PROVIDE A NEW THERAPEUTIC TARGET FOR VASCULAR CALCIFICATION IN CKD PATIENTS. 2018 2 3306 47 HIGH-PHOSPHATE-INDUCED CALCIFICATION IS RELATED TO SM22ALPHA PROMOTER METHYLATION IN VASCULAR SMOOTH MUSCLE CELLS. HYPERPHOSPHATEMIA IS CLOSELY RELATED TO VASCULAR CALCIFICATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) EXPOSED TO HIGH PHOSPHATE CONCENTRATIONS IN VITRO UNDERGO PHENOTYPIC TRANSITION TO OSTEOBLAST-LIKE CELLS. MECHANISMS UNDERLYING THIS TRANSDIFFERENTIATION ARE NOT CLEAR. IN THIS STUDY WE USED TWO IN VITRO MODELS, HUMAN AORTIC SMOOTH MUSCLE CELLS AND RAT AORTIC RINGS, TO INVESTIGATE THE PHENOTYPIC TRANSITION OF VSMCS INDUCED BY HIGH PHOSPHATE. WE FOUND THAT HIGH PHOSPHATE CONCENTRATION (3.3 MMOL/L) IN THE MEDIUM WAS ASSOCIATED WITH INCREASED DNA METHYLTRANSFERASE ACTIVITY AND METHYLATION OF THE PROMOTER REGION OF SM22ALPHA. THIS WAS ACCOMPANIED BY LOSS OF THE SMOOTH MUSCLE CELL-SPECIFIC PROTEIN SM22ALPHA, GAIN OF THE OSTEOBLAST TRANSCRIPTION FACTOR CBFA1, AND INCREASED ALKALINE PHOSPHATASE ACTIVITY WITH THE SUBSEQUENT IN VITRO CALCIFICATION. THE ADDITION OF A DEMETHYLATING AGENT (PROCAINE) TO THE HIGH-PHOSPHATE MEDIUM REDUCED DNA METHYLTRANSFERASE ACTIVITY AND PREVENTED METHYLATION OF THE SM22ALPHA PROMOTER, WHICH WAS ACCOMPANIED BY AN INCREASE IN SM22ALPHA EXPRESSION AND LESS CALCIFICATION. ADDITIONALLY, DOWNREGULATION OF SM22ALPHA, EITHER BY SIRNA OR BY A METHYL GROUP DONOR (S-ADENOSYL METHIONINE), RESULTED IN OVEREXPRESSION OF CBFA1. IN CONCLUSION, WE DEMONSTRATE THAT METHYLATION OF SM22ALPHA PROMOTER IS AN IMPORTANT EVENT IN VASCULAR SMOOTH MUSCLE CELL CALCIFICATION AND THAT HIGH PHOSPHATE INDUCES THIS EPIGENETIC MODIFICATION. THESE FINDINGS UNCOVER A NEW INSIGHT INTO MECHANISMS BY WHICH HIGH PHOSPHATE CONCENTRATION PROMOTES VASCULAR CALCIFICATION. 2010 3 3655 42 INDOXYL SULFATE ENHANCE THE HYPERMETHYLATION OF KLOTHO AND PROMOTE THE PROCESS OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A STATE OF KLOTHO DEFICIENCY. THE KLOTHO EXPRESSION MAY BE SUPPRESSED DUE TO DNA HYPERMETHYLATION IN CANCER CELLS SO WE HAVE INVESTIGATED THE EFFECTS AND POSSIBLE MECHANISMS BY WHICH KLOTHO EXPRESSION IS REGULATED IN HUMAN AORTIC SMOOTH MUSCLE CELLS (HASMCS). THE VASCULAR KLOTHO HYPERMETHYLATION IN RADIAL ARTERIES OF PATIENTS WITH END-STAGE RENAL DISEASE WAS DESCRIBED. CULTURED HASMCS AND 5/6-NEPHRECTOMIZED SPRAGUE DAWLEY (SD) RATS TREATED WITH INDOXYL SULFATE (IS) WERE USED AS IN VITRO AND IN VIVO MODELS, RESPECTIVELY. IS INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN HASMCS, AND POTENTIATED HASMCS CALCIFICATION. THE EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) 1 AND 3A IN HASMCS TREATED WITH IS WAS SIGNIFICANTLY INCREASED AND SPECIFIC INHIBITION OF DNA METHYLTRANSFERASE 1 BY 5-AZA-2'-DEOXYCYTIDINE(5AZA-2DC) CAUSED DEMETHYLATION OF THE KLOTHO GENE AND INCREASED KLOTHO EXPRESSION. IN RATS, INJECTION OF IS POTENTIATED VASCULAR CALCIFICATION, INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN THE AORTIC MEDIAL LAYER AND ALL OF THESE CHANGES COULD BE REVERTED BY 5AZA-2DC TREATMENT. TRANSCRIPTIONAL SUPPRESSION OF VASCULAR KLOTHO GENE EXPRESSION BY IS AND EPIGENETIC MODIFICATION OF KLOTHO BY IS MAY BE AN IMPORTANT PATHOLOGICAL MECHANISM OF VASCULAR CALCIFICATION IN CKD. 2016 4 3351 41 HISTONE DEMETHYLASE JARID1B REGULATES PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS IN MICE WITH CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION VIA NUCLEAR FACTOR-KAPPA B (NFKB). CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH) IS A DISORDER THAT IS CHARACTERIZED BY INCREASED PULMONARY ARTERIAL PRESSURE RESULTING FROM LUNG DISEASES OR SHORTAGE OF OXYGEN IN THE BODY. EXCESS PROLIFERATION OF PULMONARY VASCULAR CELLS SUCH AS PULMONARY ARTERY ENDOTHELIAL CELLS (PAECS) AND PULMONARY ARTERY SMOOTH MUSCLE CELLS (PASMCS) PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PH. RECENT EVIDENCE INDICATES THAT, IN ADDITION TO GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN ETIOLOGY OF PH. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE ROLE PLAYED BY JUMONJI AT-RICH INTERACTIVE DOMAIN 1B (JARID1B), A HISTONE DEMETHYLASE, IN REGULATING THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS IN CHRONIC HYPOXIA-INDUCED PH CONDITION. QUANTITATIVE POLYMERASE CHAIN REACTION ANALYSIS OF SAMPLES FROM RATS WITH PH SHOWED AN ELEVATED EXPRESSION OF JARID1B IN THEIR PASMCS, POSITIVELY CORRELATING WITH INCREASED NUCLEAR FACTOR-KAPPA B (NFKB) EXPRESSION. FURTHER FUNCTIONAL STUDIES IN VITRO INDICATED THAT OVEREXPRESSION OF JARID1B INCREASED THE PROLIFERATION AND MIGRATION OF PASMCS, WHICH WERE INHIBITED BY DEPLETION OF NFKB. GENOMEWIDE TRANSCRIPTIONAL ANALYSIS REVEALED THAT THE JARID1B REGULATED NFKB SIGNALING PATHWAY BY DIRECTLY BINDING TO ITS PROMOTER. WE HAVE ALSO SHOWN THAT JARID1B INDIRECTLY REGULATES THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR VIA NFKB SIGNALING AND HENCE MAY ALSO PLAY A CRUCIAL ROLE IN CONTROLLING PAECS, LEADING TO CHANGES IN VASCULAR ARCHITECTURE IN PH. OUR FINDINGS COULD LEAD TO FURTHER STUDIES ON THE ROLE OF JARID1B IN PH ETIOLOGY AND THEREFORE COULD LEAD TO A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC HYPOXIA INDUCED PULMONARY HYPERTENSION. 2018 5 164 37 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET. 2012 6 6665 35 UPSTREAM AND DOWNSTREAM REGULATORS OF KLOTHO EXPRESSION IN CHRONIC KIDNEY DISEASE. KLOTHO IS A CRITICAL PROTEIN THAT PROTECTS THE KIDNEY. KLOTHO IS SEVERELY DOWNREGULATED IN CHRONIC KIDNEY DISEASE (CKD), AND ITS DEFICIENCY IS IMPLICATED IN THE PATHOGENESIS AND PROGRESSION OF CKD. CONVERSELY, AN INCREASE IN KLOTHO LEVELS RESULTS IN IMPROVED KIDNEY FUNCTION AND DELAYS CKD PROGRESSION, SUPPORTING THE NOTION THAT MODULATING KLOTHO LEVELS COULD REPRESENT A POSSIBLE THERAPEUTIC STRATEGY FOR CKD TREATMENT. NEVERTHELESS, THE REGULATORY MECHANISMS RESPONSIBLE FOR THE LOSS OF KLOTHO REMAIN ELUSIVE. PREVIOUS STUDIES HAVE DEMONSTRATED THAT OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETIC MODIFICATIONS CAN MODULATE KLOTHO LEVELS. THESE MECHANISMS RESULT IN A DECREASE IN KLOTHO MRNA TRANSCRIPT LEVELS AND REDUCED TRANSLATION, THUS CAN BE GROUPED TOGETHER AS UPSTREAM REGULATORY MECHANISMS. HOWEVER, THERAPEUTIC STRATEGIES THAT AIM TO RESCUE KLOTHO LEVELS BY TARGETING THESE UPSTREAM MECHANISMS DO NOT ALWAYS RESULT IN INCREASED KLOTHO, INDICATING THE INVOLVEMENT OF OTHER REGULATORY MECHANISMS. EMERGING EVIDENCE HAS SHOWN THAT ENDOPLASMIC RETICULUM (ER) STRESS, THE UNFOLDED PROTEIN RESPONSE, AND ER-ASSOCIATED DEGRADATION ALSO AFFECT THE MODIFICATION, TRANSLOCATION, AND DEGRADATION OF KLOTHO, AND THUS ARE PROPOSED TO BE DOWNSTREAM REGULATORY MECHANISMS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF UPSTREAM AND DOWNSTREAM REGULATORY MECHANISMS OF KLOTHO AND EXAMINE POTENTIAL THERAPEUTIC STRATEGIES TO UPREGULATE KLOTHO EXPRESSION FOR CKD TREATMENT. 2023 7 273 40 AGE-INDUCED SUPPRESSION OF EZH2 MEDIATES INJURY OF PODOCYTES BY REDUCING H3K27ME3. BACKGROUND: CHRONIC HYPERGLYCEMIA, A PIVOTAL FEATURE OF DIABETES MELLITUS (DM), INITIATES THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) AND THE DYSREGULATION OF EPIGENETIC MECHANISMS, WHICH MAY CAUSE INJURY TO RENAL PODOCYTES, A CENTRAL FEATURE OF DIABETIC KIDNEY DISEASE (DKD). PREVIOUS DATA OF OUR GROUP SHOWED THAT AGES SIGNIFICANTLY REDUCE THE EXPRESSION OF NIPP1 (NUCLEAR INHIBITOR OF PROTEIN PHOSPHATASE 1) IN PODOCYTES IN VITRO AS WELL AS IN HUMAN AND MURINE DKD. NIPP1 WAS SHOWN BY OTHERS TO INTERACT WITH ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE REPRESSIVE METHYLATION OF H3K27ME3 ON HISTONE 3. THEREFORE, WE HYPOTHESIZED THAT AGES CAN DIRECTLY INDUCE EPIGENETIC CHANGES IN PODOCYTES. METHODS: WE ANALYZED THE RELEVANCE OF AGES ON EZH2 EXPRESSION AND ACTIVITY IN A MURINE PODOCYTE CELL LINE. CELLS WERE TREATED WITH 5 MG/ML GLYCATED BSA FOR 24 H. TO DETERMINE THE MEANING OF EZH2 SUPPRESSION, EZH2 ACTIVITY WAS INHIBITED BY INCUBATING THE CELLS WITH THE PHARMACOLOGICAL METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A; EZH2 EXPRESSION WAS REPRESSED WITH SIRNA. MRNA EXPRESSION WAS ANALYZED WITH REAL-TIME PCR, AND PROTEIN EXPRESSION WITH WESTERN BLOT. EZH2 EXPRESSION AND LEVEL OF H3K27 TRIMETHYLATION IN PODOCYTES OF DIABETIC DB/DB MICE, A MOUSE MODEL FOR TYPE 2 DM, WERE ANALYZED USING IMMUNOFLUORESCENCE. RESULTS: OUR DATA DEMONSTRATED THAT AGES DECREASE EZH2 EXPRESSION IN PODOCYTES AND CONSEQUENTLY REDUCE H3K27ME3. THIS SUPPRESSION OF EZH2 MIMICKED THE AGE EFFECTS AND CAUSED AN UPREGULATED EXPRESSION OF PATHOLOGICAL FACTORS THAT CONTRIBUTE TO PODOCYTE INJURY IN DKD. IN ADDITION, ANALYSES OF DB/DB MICE SHOWED SIGNIFICANTLY REDUCED H3K27ME3 AND EZH2 EXPRESSION IN PODOCYTES. MOREOVER, THE SUPPRESSION OF NIPP1 AND EZH2 SHOWED SIMILAR EFFECTS REGARDING PODOCYTE INJURY. CONCLUSIONS: OUR STUDIES PROVIDE A NOVEL PATHWAY HOW AGES CONTRIBUTE TO PODOCYTE INJURY AND THE FORMATION OF THE SO-CALLED METABOLIC MEMORY IN DKD. 2020 8 3887 24 KLOTHO METHYLATION IS LINKED TO UREMIC TOXINS AND CHRONIC KIDNEY DISEASE. EPIGENETIC REGULATION PLAYS A MAJOR ROLE IN UREMIC TOXIN-INDUCED CHRONIC KIDNEY DISEASE (CKD) PROGRESSION. THE KLOTHO PROTEIN IS A KEY MODULATOR OF HOMEOSTASIS IN RENAL FUNCTION. UREMIC TOXIN ACCUMULATION CAN INDUCE DNA METHYLTRANSFERASE (DNMT) PROTEIN EXPRESSION, WHICH IS INVOLVED IN THE SILENCING OF KLOTHO THROUGH HYPERMETHYLATION. TREATMENT WITH DNMT INHIBITORS CAN INDUCE A HYPERMETHYLATED STATUS OF KLOTHO AND SUPPRESS MRNA AND PROTEIN EXPRESSION. EPIGENETIC TARGETING OF SPECIFIC GENES MAY BECOME AN EFFECTIVE STRATEGY TO PREVENT PROGRESSION OF UREMIA-RELATED CKD. 2012 9 6700 36 VASCULAR CALCIFICATION MECHANISMS: UPDATES AND RENEWED INSIGHT INTO SIGNALING PATHWAYS INVOLVED IN HIGH PHOSPHATE-MEDIATED VASCULAR SMOOTH MUSCLE CELL CALCIFICATION. VASCULAR CALCIFICATION (VC) IS ASSOCIATED WITH AGING, CARDIOVASCULAR AND RENAL DISEASES AND RESULTS IN POOR MORBIDITY AND INCREASED MORTALITY. VC OCCURS IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), A CONDITION THAT IS ASSOCIATED WITH HIGH SERUM PHOSPHATE (PI) AND SEVERE CARDIOVASCULAR CONSEQUENCES. HIGH SERUM PI LEVEL IS RELATED TO SOME PATHOLOGIES WHICH AFFECT THE BEHAVIOUR OF VASCULAR CELLS, INCLUDING PLATELETS, ENDOTHELIAL CELLS (ECS) AND SMOOTH MUSCLE CELLS (SMCS), AND PLAYS A CENTRAL ROLE IN PROMOTING VC. VC IS A COMPLEX, ACTIVE AND CELL-MEDIATED PROCESS INVOLVING THE TRANSDIFFERENTIATION OF VASCULAR SMCS TO A BONE-LIKE PHENOTYPE, SYSTEMIC INFLAMMATION, DECREASED ANTI-CALCIFIC EVENTS (LOSS OF CALCIFICATION INHIBITORS), LOSS IN SMC LINEAGE MARKERS AND ENHANCED PRO-CALCIFIC MICRORNAS (MIRS), AN INCREASED INTRACELLULAR CALCIUM LEVEL, APOPTOSIS, ABERRANT DNA DAMAGE RESPONSE (DDR) AND SENESCENCE OF VASCULAR SMCS. THIS REVIEW GIVES A BRIEF OVERVIEW OF THE CURRENT KNOWLEDGE OF VC MECHANISMS WITH A PARTICULAR FOCUS ON PI-INDUCED CHANGES IN THE VASCULAR WALL IMPORTANT IN PROMOTING CALCIFICATION. IN ADDITION TO REVIEWING THE MAIN FINDINGS, THIS REVIEW ALSO SHEDS LIGHT ON DIRECTIONS FOR FUTURE RESEARCH IN THIS AREA AND DISCUSSES EMERGING PATHWAYS SUCH AS PI-REGULATED INTRACELLULAR CALCIUM SIGNALING, EPIGENETICS, OXIDATIVE DNA DAMAGE AND SENESCENCE-MEDIATED MECHANISMS THAT MAY PLAY CRITICAL, YET TO BE EXPLORED, REGULATORY AND DRUGGABLE ROLES IN LIMITING VC. 2021 10 3527 30 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 11 3431 43 HYDROGEN SULFIDE ALLEVIATES HYPERTENSIVE KIDNEY DYSFUNCTION THROUGH AN EPIGENETIC MECHANISM. HYPERTENSION IS A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD), AND RENAL INFLAMMATION IS AN INTEGRAL PART IN THIS PATHOLOGY. HYDROGEN SULFIDE (H(2)S) HAS BEEN SHOWN TO MITIGATE RENAL DAMAGE THROUGH REDUCTION IN BLOOD PRESSURE AND ROS; HOWEVER, THE EXACT MECHANISMS ARE NOT CLEAR. WHILE SEVERAL STUDIES HAVE UNDERLINED THE ROLE OF EPIGENETICS IN RENAL INFLAMMATION AND DYSFUNCTION, THE MECHANISMS THROUGH WHICH EPIGENETIC REGULATORS PLAY A ROLE IN HYPERTENSION ARE NOT WELL DEFINED. IN THIS STUDY, WE SOUGHT TO IDENTIFY WHETHER MICRORNAS ARE DYSREGULATED IN RESPONSE TO ANGIOTENSIN II (ANG II)-INDUCED HYPERTENSION IN THE KIDNEY AND WHETHER A H(2)S DONOR, GYY4137, COULD REVERSE THE MICRORNA ALTERATION AND KIDNEY FUNCTION. WILD-TYPE (C57BL/6J) MICE WERE TREATED WITHOUT OR WITH ANG II AND GYY4137 FOR 4 WK. BLOOD PRESSURE, RENAL BLOOD FLOW, AND RESISTIVE INDEX (RI) WERE MEASURED. MICRORNA MICROARRAYS WERE CONDUCTED AND SUBSEQUENT TARGET PREDICTION REVEALED GENES ASSOCIATED WITH A PROINFLAMMATORY RESPONSE. ANG II TREATMENT SIGNIFICANTLY INCREASED BLOOD PRESSURE, DECREASED BLOOD FLOW IN THE RENAL CORTEX, INCREASED RI, AND REDUCED RENAL FUNCTION. THESE EFFECTS WERE AMELIORATED IN MICE TREATED WITH GYY4137. MICROARRAY ANALYSIS REVEALED DOWNREGULATION OF MIR-129 IN ANG II-TREATED MICE AND UPREGULATION AFTER GYY4137 TREATMENT. QUANTITATION OF PROTEINS INVOLVED IN THE INFLAMMATORY RESPONSE AND DNA METHYLATION REVEALED UPREGULATION OF IL-17A AND DNA METHYLTRANSFERASE 3A, WHEREAS H(2)S PRODUCTION ENZYMES AND ANTI-INFLAMMATORY IL-10 WERE REDUCED. TAKEN TOGETHER, OUR DATA SUGGEST THAT DOWNREGULATION OF MIR-129 PLAYS A SIGNIFICANT ROLE IN ANG II-INDUCED RENAL INFLAMMATION AND FUNCTIONAL OUTCOMES AND THAT GYY4137 IMPROVES RENAL FUNCTION BY REVERSING MIR-129 EXPRESSION.NEW & NOTEWORTHY WE INVESTIGATED EPIGENETIC CHANGES THAT OCCUR IN THE HYPERTENSIVE KIDNEY AND HOW H(2)S SUPPLEMENTATION REVERSES ADVERSE EFFECTS. INFLAMMATION, ABERRANT METHYLATION, AND DYSFUNCTION WERE OBSERVED IN THE HYPERTENSIVE KIDNEY, AND THESE EFFECTS WERE ALLEVIATED WITH H(2)S SUPPLEMENTATION. WE IDENTIFY MIR-129 AS A POTENTIAL REGULATOR OF BLOOD PRESSURE AND H(2)S REGULATION. 2017 12 4159 35 MECP2 CONTROLS AN EPIGENETIC PATHWAY THAT PROMOTES MYOFIBROBLAST TRANSDIFFERENTIATION AND FIBROSIS. BACKGROUND & AIMS: MYOFIBROBLAST TRANSDIFFERENTIATION GENERATES HEPATIC MYOFIBROBLASTS, WHICH PROMOTE LIVER FIBROGENESIS. THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARGAMMA) IS A NEGATIVE REGULATOR OF THIS PROCESS. WE INVESTIGATED EPIGENETIC REGULATION OF PPARGAMMA AND MYOFIBROBLAST TRANSDIFFERENTIATION. METHODS: CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS ASSESSED THE BINDING OF METHYL-CPG BINDING PROTEIN 2 (MECP2) TO PPARGAMMA AND CHROMATIN MODIFICATIONS THAT SILENCE THIS GENE. MECP2(-/Y) MICE AND AN INHIBITOR (DZNEP) OF THE EPIGENETIC REGULATORY PROTEIN EZH2 WERE USED IN THE CARBON TETRACHLORIDE MODEL OF LIVER FIBROSIS. LIVER TISSUES FROM MICE WERE ASSESSED BY HISTOLOGIC ANALYSIS; MARKERS OF FIBROSIS WERE MEASURED BY QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR). REVERSE TRANSCRIPTION PCR DETECTED CHANGES IN EXPRESSION OF THE MICRORNA MIR132 AND ITS TARGET, ELONGATED TRANSCRIPTS OF MECP2. MYOFIBROBLASTS WERE TRANSFECTED WITH MIR132; PPARGAMMA AND MECP2 EXPRESSIONS WERE ANALYZED BY QPCR OR IMMUNOBLOTTING. RESULTS: MYOFIBROBLAST TRANSDIFFERENTIATION OF HEPATIC STELLATE CELLS IS CONTROLLED BY A COMBINATION OF MECP2, EZH2, AND MIR132 IN A RELAY PATHWAY. THE PATHWAY IS ACTIVATED BY DOWN-REGULATION OF MIR132, RELEASING THE TRANSLATIONAL BLOCK ON MECP2. MECP2 IS RECRUITED TO THE 5' END OF PPARGAMMA, WHERE IT PROMOTES METHYLATION BY H3K9 AND RECRUITS THE TRANSCRIPTION REPRESSOR HP1ALPHA. MECP2 ALSO STIMULATES EXPRESSION OF EZH2 AND METHYLATION OF H3K27 TO FORM A REPRESSIVE CHROMATIN STRUCTURE IN THE 3' EXONS OF PPARGAMMA. GENETIC AND PHARMACOLOGIC DISRUPTIONS OF MECP2 OR EZH2 REDUCED THE FIBROGENIC CHARACTERISTICS OF MYOFIBROBLASTS AND ATTENUATED FIBROGENESIS. CONCLUSIONS: LIVER FIBROSIS IS REGULATED BY AN EPIGENETIC RELAY PATHWAY THAT INCLUDES MECP2, EZH2, AND MIR132. REAGENTS THAT INTERFERE WITH THIS PATHWAY MIGHT BE DEVELOPED TO REDUCE FIBROGENESIS IN CHRONIC LIVER DISEASE. 2010 13 141 35 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 14 446 36 APABETALONE DOWNREGULATES FIBROTIC, INFLAMMATORY AND CALCIFIC PROCESSES IN RENAL MESANGIAL CELLS AND PATIENTS WITH RENAL IMPAIRMENT. EPIGENETIC MECHANISMS ARE IMPLICATED IN TRANSCRIPTIONAL PROGRAMS DRIVING CHRONIC KIDNEY DISEASE (CKD). APABETALONE IS AN ORALLY AVAILABLE INHIBITOR OF BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS, WHICH ARE EPIGENETIC READERS THAT MODULATE GENE EXPRESSION. IN THE PHASE 3 BETONMACE TRIAL, APABETALONE REDUCED RISK OF MAJOR ADVERSE CARDIAC EVENTS (MACE) BY 50% IN THE CKD SUBPOPULATION, INDICATING FAVORABLE EFFECTS ALONG THE KIDNEY-HEART AXIS. ACTIVATION OF HUMAN RENAL MESANGIAL CELLS (HRMCS) TO A CONTRACTILE PHENOTYPE THAT OVERPRODUCES EXTRACELLULAR MATRIX (ECM) AND INFLAMMATORY CYTOKINES, AND PROMOTES CALCIFICATION, FREQUENTLY ACCOMPANIES CKD TO DRIVE PATHOLOGY. HERE, WE SHOW APABETALONE DOWNREGULATED HRMC ACTIVATION WITH TGF-BETA1 STIMULATION BY SUPPRESSING TGF-BETA1-INDUCED ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION, ALPHA-SMA ASSEMBLY INTO STRESS FIBERS, ENHANCED CONTRACTION, COLLAGEN OVERPRODUCTION, AND EXPRESSION OF KEY DRIVERS OF FIBROSIS, INFLAMMATION, OR CALCIFICATION INCLUDING THROMBOSPONDIN, FIBRONECTIN, PERIOSTIN, SPARC, INTERLEUKIN 6, AND ALKALINE PHOSPHATASE. LIPOPOLYSACCHARIDE-STIMULATED EXPRESSION OF INFLAMMATORY GENES IL6, IL1B, AND PTGS2 WAS ALSO SUPPRESSED. TRANSCRIPTOMICS CONFIRMED APABETALONE AFFECTED GENE SETS OF ECM REMODELING AND INTEGRINS. CLINICAL TRANSLATION OF IN VITRO RESULTS WAS INDICATED IN CKD PATIENTS WHERE A SINGLE DOSE OF APABETALONE REDUCED PLASMA LEVELS OF KEY PRO-FIBROTIC AND INFLAMMATORY MARKERS, AND INDICATED INHIBITION OF TGF-BETA1 SIGNALING. WHILE PLASMA PROTEINS CANNOT BE TRACED TO THE KIDNEY ALONE, ANTI-FIBROTIC AND ANTI-INFLAMMATORY EFFECTS OF APABETALONE IDENTIFIED IN THIS STUDY ARE CONSISTENT WITH THE OBSERVED DECREASE IN CARDIOVASCULAR RISK IN CKD PATIENTS. 2023 15 6431 33 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION. 2018 16 5972 25 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 17 5571 29 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY. 2013 18 4362 38 MIR?152 REGULATES TGF?BETA1?INDUCED EPITHELIAL?MESENCHYMAL TRANSITION BY TARGETING HPIP IN TUBULAR EPITHELIAL CELLS. RENAL FIBROSIS IS A COMMON PATHOLOGICAL FEATURE OF CHRONIC KIDNEY DISEASES, AND THEIR DEVELOPMENT AND PROGRESSION ARE INFLUENCED BY EPIGENETIC MODIFICATIONS INCLUDING ABERRANT MICRORNA (MIRNA OR MIR) EXPRESSION. MIRNAS HAVE BEEN DEMONSTRATED TO MODULATE THE AGGRESSIVENESS OF VARIOUS CANCERS AND HAVE EMERGED AS POSSIBLE THERAPEUTIC AGENTS FOR THE MANAGEMENT OF RENAL FIBROSIS. TRANSFORMING GROWTH FACTOR BETA1 (TGF?BETA1)?INDUCED EPITHELIAL?MESENCHYMAL TRANSITION (EMT) OF TUBULAR EPITHELIAL CELLS SERVES A ROLE IN THE INITIATION AND PROGRESSION OF RENAL FIBROSIS. FURTHERMORE, RECENT RESULTS INDICATED THAT THE PROGRESSION OF EMT IS REVERSIBLE. THE PRESENT STUDY AIMED TO CLARIFY THE ROLE OF MIR?152 IN EMT OF THE TUBULAR EPITHELIAL CELL LINE HK?2, STIMULATED BY TGF?BETA1, USING IN VITRO TRANSFECTION WITH A MIR?152 MIMIC AND TO FURTHER INVESTIGATE THE UNDERLYING MECHANISM OF MIR?152 ACTIVITY. IN THE PRESENT STUDY, MIR?152 EXPRESSION WAS SIGNIFICANTLY REDUCED IN TGF?BETA1?TREATED HK?2 CELLS, ACCOMPANIED BY AN INCREASED EXPRESSION OF HEMATOPOIETIC PRE?B?CELL LEUKEMIA TRANSCRIPTION FACTOR (PBX)?INTERACTING PROTEIN (HPIP). ADDITIONALLY, MIR?152 OVEREXPRESSION INHIBITED TGF?BETA1?INDUCED EMT AND SUPPRESSED HPIP EXPRESSION BY DIRECTLY TARGETING THE 3' UNTRANSLATED REGION OF HPIP IN HK?2 CELLS. FURTHERMORE, UPREGULATION OF HPIP REVERSED MIR?152?MEDIATED INHIBITORY EFFECTS ON THE EMT. COLLECTIVELY, THE RESULTS SUGGEST THAT DOWNREGULATION OF MIR?152 INITIATES THE DEDIFFERENTIATION OF RENAL TUBULES AND PROGRESSION OF RENAL FIBROSIS, WHICH MAY PROVIDE IMPORTANT TARGETS FOR PREVENTION STRATEGIES OF RENAL FIBROSIS. 2018 19 3519 37 IGF-1 SIGNALING IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION: ROLE OF EPIGENETIC REGULATION. PULMONARY HYPERTENSION IS A FATAL DISEASE CHARACTERIZED BY A PROGRESSIVE INCREASE IN PULMONARY ARTERY PRESSURE ACCOMPANIED BY PULMONARY VASCULAR REMODELING AND INCREASED VASOMOTOR TONE. ALTHOUGH SOME BIOLOGICAL PATHWAYS HAVE BEEN IDENTIFIED IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH), LITTLE IS KNOWN REGARDING THE ROLE OF GROWTH FACTORS IN THE PATHOGENESIS OF PH IN NEONATES. IN THIS STUDY, USING A MODEL OF HYPOXIA-INDUCED PH IN NEONATAL MICE, WE DEMONSTRATE THAT THE GROWTH FACTOR INSULIN-LIKE GROWTH FACTOR-1 (IGF-1), A POTENT ACTIVATOR OF THE AKT SIGNALING PATHWAY, IS INVOLVED IN NEONATAL PH. AFTER EXPOSURE TO HYPOXIA, IGF-1 SIGNALING IS ACTIVATED IN PULMONARY ENDOTHELIAL AND SMOOTH MUSCLE CELLS IN VITRO, AND THE IGF-1 DOWNSTREAM SIGNAL PAKT(S473) IS UPREGULATED IN LUNGS OF NEONATAL MICE. WE FOUND THAT IGF-1 REGULATES ET-1 EXPRESSION IN PULMONARY ENDOTHELIAL CELLS AND THAT IGF-1 EXPRESSION IS REGULATED BY HISTONE DEACETYLASES (HDACS). IN ADDITION, THERE IS A DIFFERENTIAL CYTOSINE METHYLATION SITE IN THE IGF-1 PROMOTER REGION IN RESPONSE TO NEONATAL HYPOXIA. MOREOVER, INHIBITION OF HDACS WITH APICIDIN DECREASES NEONATAL HYPOXIA-INDUCED GLOBAL DNA METHYLATION LEVELS IN LUNGS AND SPECIFIC CYTOSINE METHYLATION LEVELS AROUND THE PULMONARY IGF-1 PROMOTER REGION. FINALLY, HDAC INHIBITION WITH APICIDIN REDUCES CHRONIC HYPOXIA-INDUCED ACTIVATION OF IGF-1/PAKT SIGNALING IN LUNGS AND ATTENUATES RIGHT VENTRICULAR HYPERTROPHY AND PULMONARY VASCULAR REMODELING. TAKEN TOGETHER, WE CONCLUDE THAT IGF-1, WHICH IS EPIGENETICALLY REGULATED, IS INVOLVED IN THE PATHOGENESIS OF PULMONARY HYPERTENSION IN NEONATAL MICE. THIS STUDY IMPLICATES A NOVEL HDAC/IGF-1 EPIGENETIC PATHWAY IN THE REGULATION OF HYPOXIA-INDUCED PH AND WARRANTS FURTHER STUDY OF THE ROLE OF IGF-1 IN NEONATAL PULMONARY HYPERTENSIVE DISEASE. 2015 20 6511 27 TRANSCRIPTION FACTORS AS THERAPEUTIC TARGETS IN CHRONIC KIDNEY DISEASE. THE GROWING NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS RECOGNIZED AS AN EMERGING PROBLEM WORLDWIDE. RECENT STUDIES HAVE INDICATED THAT DEREGULATION OF TRANSCRIPTION FACTORS IS ASSOCIATED WITH THE ONSET OR PROGRESSION OF KIDNEY DISEASE. SEVERAL CLINICAL TRIALS INDICATED THAT REGRESSION OF CKD MAY BE FEASIBLE VIA ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR ERYTHROID-2 RELATED FACTOR 2 (NRF2), WHICH SUGGESTS THAT TRANSCRIPTION FACTORS MAY BE POTENTIAL DRUG TARGETS FOR CKD. AGENTS STABILIZING HYPOXIA-INDUCIBLE FACTOR (HIF), WHICH MAY BE BENEFICIAL FOR RENAL ANEMIA AND RENAL PROTECTION, ARE ALSO NOW UNDER CLINICAL TRIAL. RECENTLY, WE HAVE REPORTED THAT THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4) REGULATES THE GLOMERULAR PODOCYTE EPIGENOME, AND THAT THE ANTIPROTEINURIC EFFECT OF THE RENIN(-)ANGIOTENSIN SYSTEM BLOCKADE MAY BE PARTIALLY MEDIATED BY KLF4. KLF4 IS ONE OF THE YAMANAKA FACTORS THAT INDUCES IPS CELLS AND IS REPORTED TO BE INVOLVED IN EPIGENETIC REMODELING. IN THIS ARTICLE, WE SUMMARIZE THE TRANSCRIPTION FACTORS ASSOCIATED WITH CKD AND PARTICULARLY FOCUS ON THE POSSIBILITY OF TRANSCRIPTION FACTORS BEING NOVEL DRUG TARGETS FOR CKD THROUGH EPIGENETIC MODULATION. 2018