1 6717 124 VITAMIN B SUPPLEMENTATION AND NUTRITIONAL INTAKE OF METHYL DONORS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A CRITICAL REVIEW OF THE IMPACT ON EPIGENETIC MACHINERY. CARDIOVASCULAR MORBIDITY AND MORTALITY ARE SEVERAL-FOLD HIGHER IN PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD) THAN IN THE GENERAL POPULATION. HYPERHOMOCYSTEINEMIA HAS UNDOUBTEDLY A CENTRAL ROLE IN SUCH A PROMINENT CARDIOVASCULAR BURDEN. THE LEVELS OF HOMOCYSTEINE ARE REGULATED BY METHYL DONORS (FOLATE, METHIONINE, CHOLINE, BETAINE), AND COFACTORS (VITAMIN B6, VITAMIN B12,). UREMIA-INDUCED HYPERHOMOCYSTEINEMIA HAS AS ITS MAIN TARGETS DNA METHYLTRANSFERASES, AND THIS LEADS TO AN ALTERED EPIGENETIC CONTROL OF GENES REGULATED THROUGH METHYLATION. IN RENAL PATIENTS, THE EPIGENETIC LANDSCAPE IS STRICTLY CORRELATED WITH THE UREMIC PHENOTYPE AND DEPENDENT ON DIETARY INTAKE OF MICRONUTRIENTS, INFLAMMATION, GUT MICROBIOME, INFLAMMATORY STATUS, OXIDATIVE STRESS, AND LIFESTYLE HABITS. ALL THESE FACTORS ARE KEY CONTRIBUTORS IN METHYLOME MAINTENANCE AND IN THE MODULATION OF GENE TRANSCRIPTION THROUGH DNA HYPO- OR HYPERMETHYLATION IN CKD. THIS IS AN OVERVIEW OF THE EPIGENETIC CHANGES RELATED TO DNA METHYLATION IN PATIENTS WITH ADVANCED CKD AND ESRD. WE EXPLORED THE CURRENTLY AVAILABLE DATA ON THE MOLECULAR DYSREGULATIONS RESULTING FROM ALTERED GENE EXPRESSION IN UREMIA. SPECIAL ATTENTION WAS PAID TO THE EFFICACY OF B-VITAMINS SUPPLEMENTATION AND DIETARY INTAKE OF METHYL DONORS ON HOMOCYSTEINE LOWERING AND CARDIOVASCULAR PROTECTION. 2020 2 4217 40 METHYL DONOR NUTRIENTS IN CHRONIC KIDNEY DISEASE: IMPACT ON THE EPIGENETIC LANDSCAPE. EPIGENETIC ALTERATIONS, SUCH AS THOSE LINKED TO DNA METHYLATION, MAY POTENTIALLY PROVIDE MOLECULAR EXPLANATIONS FOR COMPLICATIONS ASSOCIATED WITH ALTERED GENE EXPRESSION IN ILLNESSES, SUCH AS CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH BOTH DNA HYPO- AND HYPERMETHYLATION HAVE BEEN OBSERVED IN THE UREMIC MILIEU, THIS REMAINS ONLY A SINGLE ASPECT OF THE EPIGENETIC LANDSCAPE AND, THUS, OF ANY BIOCHEMICAL DYSREGULATION ASSOCIATED WITH CKD. NEVERTHELESS, THE ROLE OF UREMIA-PROMOTING ALTERATIONS ON THE EPIGENETIC LANDSCAPE REGULATING GENE EXPRESSION IS STILL A NOVEL AND SCARCELY STUDIED FIELD. ALTHOUGH FEW STUDIES HAVE ACTUALLY REPORTED ALTERATIONS OF DNA METHYLATION VIA METHYL DONOR NUTRIENT INTAKE, EMERGING EVIDENCE INDICATES THAT NUTRITIONAL MODIFICATION OF THE MICROBIOME CAN AFFECT ONE-CARBON METABOLISM AND THE CAPACITY TO METHYLATE THE GENOME IN CKD. IN THIS REVIEW, WE DISCUSS THE NUTRITIONAL MODIFICATIONS THAT MAY AFFECT ONE-CARBON METABOLISM AND THE POSSIBLE IMPACT OF METHYL DONOR NUTRIENTS ON THE MICROBIOME, CKD, AND ITS PHENOTYPE. 2019 3 2833 29 FOLATE AND DNA METHYLATION: A REVIEW OF MOLECULAR MECHANISMS AND THE EVIDENCE FOR FOLATE'S ROLE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION CRITICAL TO NORMAL GENOME REGULATION AND DEVELOPMENT. THE VITAMIN FOLATE IS A KEY SOURCE OF THE ONE CARBON GROUP USED TO METHYLATE DNA. BECAUSE NORMAL MAMMALIAN DEVELOPMENT IS DEPENDENT ON DNA METHYLATION, THERE IS ENORMOUS INTEREST IN ASSESSING THE POTENTIAL FOR CHANGES IN FOLATE INTAKE TO MODULATE DNA METHYLATION BOTH AS A BIOMARKER FOR FOLATE STATUS AND AS A MECHANISTIC LINK TO DEVELOPMENTAL DISORDERS AND CHRONIC DISEASES INCLUDING CANCER. THIS REVIEW HIGHLIGHTS THE ROLE OF DNA METHYLATION IN NORMAL GENOME FUNCTION, HOW IT CAN BE ALTERED, AND THE EVIDENCE OF THE ROLE OF FOLATE/FOLIC ACID IN THESE PROCESSES. 2012 4 462 30 ARE ALTERATIONS IN DNA METHYLATION RELATED TO CKD DEVELOPMENT? THE MODIFICATIONS IN GENOMIC DNA METHYLATION ARE INVOLVED IN THE REGULATION OF NORMAL AND PATHOLOGICAL CELLULAR PROCESSES. THE EPIGENETIC REGULATION STIMULATES BIOLOGICAL PLASTICITY AS AN ADAPTIVE RESPONSE TO VARIATIONS IN ENVIRONMENTAL FACTORS. THE ROLE OF EPIGENETIC CHANGES IS VITAL FOR THE DEVELOPMENT OF SOME DISEASES, INCLUDING ATHEROGENESIS, CANCERS, AND CHRONIC KIDNEY DISEASE (CKD). THE RESULTS OF STUDIES PRESENTED IN THIS REVIEW HAVE SUGGESTED THAT ALTERED DNA METHYLATION CAN MODULATE THE EXPRESSION OF PRO-INFLAMMATORY AND PRO-FIBROTIC GENES, AS WELL THOSE ESSENTIAL FOR KIDNEY DEVELOPMENT AND FUNCTION, THUS STIMULATING RENAL DISEASE PROGRESSION. ABNORMALLY INCREASED HOMOCYSTEINE, HYPOXIA, AND INFLAMMATION HAVE BEEN SUGGESTED TO ALTER EPIGENETIC REGULATION OF GENE EXPRESSION IN CKD. STUDIES OF RENAL SAMPLES HAVE DEMONSTRATED THE RELATIONSHIP BETWEEN VARIATIONS IN DNA METHYLATION AND FIBROSIS AND VARIATIONS IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) IN HUMAN CKD. THE UNRAVELLING OF THE GENETIC-EPIGENETIC PROFILE WOULD ENHANCE OUR UNDERSTANDING OF PROCESSES UNDERLYING THE DEVELOPMENT OF CKD. THE UNDERSTANDING OF MULTIFACETED RELATIONSHIP BETWEEN DNA METHYLATION, GENES EXPRESSION, AND DISEASE DEVELOPMENT AND PROGRESSION COULD IMPROVE THE ABILITY TO IDENTIFY INDIVIDUALS AT RISK OF CKD AND ENABLE THE CHOICE OF APPROPRIATE DISEASE MANAGEMENT. 2022 5 2539 43 EPIGENETICS IN HYPERHOMOCYSTEINEMIC STATES. A SPECIAL FOCUS ON UREMIA. AIM OF THIS ARTICLE IS TO REVIEW THE TOPIC OF EPIGENETIC CONTROL OF GENE EXPRESSION, ESPECIALLY REGARDING DNA METHYLATION, IN CHRONIC KIDNEY DISEASE AND UREMIA. HYPERHOMOCYSTEINEMIA IS CONSIDERED AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ALTHOUGH THE MOST RECENT INTERVENTION STUDIES UTILIZING FOLIC ACID ARE NEGATIVE. THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH IS ITSELF CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. THE EXTENT OF METHYLATION INHIBITION OF EACH INDIVIDUAL METHYLTRANSFERASE DEPENDS ON THE METHYL DONOR S-ADENOSYLMETHIONINE (ADOMET) AVAILABILITY, ON THE [ADOMET]/[ADOHCY] RATIO, AND ON THE INDIVIDUAL KM VALUE FOR ADOMET AND KI FOR ADOHCY. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, ALMOST UNEQUIVOCALLY SHOW. IN VIVO, DNA METHYLATION MAY BE ALSO INFLUENCED BY VARIOUS FACTORS IN DIFFERENT TISSUES, FOR EXAMPLE BY RATE OF CELL GROWTH, FOLATE STATUS, ETC. AND IMPORTANTLY INFLAMMATION. IN CHRONIC KIDNEY DISEASE AND IN UREMIA, HYPERHOMOCYSTEINEMIA IS COMMONLY SEEN, AND CAN BE ASSOCIATED WITH GLOBAL DNA HYPOMETHYLATION, AND WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION. THIS ALTERATION IS SUSCEPTIBLE OF REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. IF THIS ABNORMALITY WILL TRANSLATE ITSELF IN ALTERATIONS OF EXPRESSION OF GENES RELEVANT TO THE PATHOGENESIS OF THIS DISEASE STILL REMAINS TO BE ESTABLISHED. IN ADDITION, THESE RESULTS ESTABLISH A LINK BETWEEN THE EPIGENETIC CONTROL OF GENE EXPRESSION AND XENOBIOTIC INFLUENCES, SUCH AS FOLATE THERAPY. 2009 6 1515 36 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 7 315 33 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 8 1060 42 CLINICAL RELEVANCE OF EPIGENETIC DYSREGULATION IN CHRONIC KIDNEY DISEASE-ASSOCIATED CARDIOVASCULAR DISEASE. ACROSS THE SPECTRUM OF CLINICAL MEDICINE, THE FIELD OF EPIGENETICS HAS GAINED SUBSTANTIAL SCIENTIFIC INTEREST IN RECENT YEARS. EPIGENETICS REFERS TO MODIFICATIONS IN GENE EXPRESSION WHICH ARE NOT EXPLAINED BY CHANGES IN DNA SEQUENCE. CLASSICAL COMPONENTS OF EPIGENETIC REGULATION COMPRISE DNA METHYLATION, HISTONE MODIFICATIONS AND RNA INTERFERENCE. IN CHRONIC KIDNEY DISEASE (CKD), SEVERAL FEATURES OF URAEMIA, SUCH AS HYPERHOMOCYSTEINEMIA AND INFLAMMATION, MAY CONTRIBUTE TO CHANGES IN EPIGENETIC GENE REGULATION. IT HAS BEEN SUGGESTED THAT THESE CHANGES MAY AFFECT GENES RELATED TO CARDIOVASCULAR DISEASE. THEREBY, A URAEMIA-ASSOCIATED DISTURBANCE IN EPIGENETIC REGULATION MAY CONTRIBUTE TO THE SUBSTANTIAL INCREASE IN CARDIOVASCULAR MORBIDITY IN CKD PATIENTS. THE PRESENT REVIEW AIMS TO SUMMARIZE CURRENT KNOWLEDGE OF EPIGENETIC DYSREGULATION IN CARDIOVASCULAR DISEASE FROM A NEPHROLOGICAL PERSPECTIVE, WITH A SPECIAL FOCUS ON DNA METHYLATION. WE FIRST DESCRIBE THE IMPACT OF ALTERED EPIGENETIC REGULATION IN NON-CKD-ASSOCIATED ARTERIOSCLEROSIS, AND NEXT CHARACTERIZE URAEMIC FEATURES WHICH MAY AFFECT EPIGENETIC GENE REGULATION IN THE CONTEXT OF CARDIOVASCULAR DISEASE. FINALLY, WE CONCLUDE THAT SUBSTANTIAL ADDITIONAL WORK IS NEEDED BEFORE EPIGENETIC REGULATORY MECHANISMS MAY BECOME THERAPEUTIC TARGETS IN CKD-ASSOCIATED CARDIOVASCULAR DISEASE. 2013 9 2154 38 EPIGENETIC MECHANISMS AND KIDNEY DISEASES. IN RECENT YEARS, MOLECULAR RESEARCH HAS BROUGHT TO LIGHT A SERIES OF MECHANISMS INVOLVED IN THE REGULATION OF GENE FUNCTION WITHOUT ALTERING THE DNA SEQUENCE. THESE MECHANISMS ARE DESCRIBED WITH THE TERM "EPIGENETICS" AND INCLUDE MODIFICATIONS IN THE STRUCTURE OF THE HUMAN GENOME, LEADING TO HERITABLE AND POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION. THERE IS NOW INCREASING EVIDENCE SUGGESTING THAT SEVERAL CHARACTERISTIC FEATURES OF CHRONIC KIDNEY DISEASE SUCH AS HYPERHOMOCYSTEINEMIA, SUBCLINICAL INFLAMMATION, INCREASED OXIDATIVE STRESS AND OTHERS MAY AFFECT THE HUMAN EPIGENOME. IN ADDITION, ANIMAL STUDIES HAVE SUGGESTED A POSSIBLE LINK BETWEEN NUTRITION AND ENVIRONMENTAL EXPOSURE DURING THE PERICONCEPTIONAL PERIOD AND EPIGENETIC CHANGES IN THE EXPRESSION OF MAJOR GENES IMPLICATED IN KIDNEY ORGANOGENESIS; THESE CHANGES RESULT IN A DIMINISHED NUMBER OF NEPHRONS IN THE DEVELOPING KIDNEY, WHICH PREDISPOSES TO AN INCREASED RISK FOR HYPERTENSION AND CHRONIC KIDNEY DISEASE IN FUTURE LIFE. THE UNDERSTANDING OF THE ROLE OF EPIGENETIC PHENOMENA IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE OPENS NEW AVENUES FOR FUTURE THERAPEUTIC STRATEGIES, THROUGH THE DEVELOPMENT OF PHARMACEUTICAL AGENTS THAT TARGET DIRECTLY WITH THE CHANGES IN THE HUMAN EPIGENOME. SUCH EPIGENETIC DRUGS ARE ALREADY IN CLINICAL USE FOR THE TREATMENT OF CANCER AS WELL AS UNDER INVESTIGATION FOR THE USE IN OTHER DISEASES. THIS REVIEW WILL SUMMARIZE THE EXISTING DATA ON THE LINK BETWEEN EPIGENETIC MECHANISMS AND CHRONIC UREMIC MILIEU, AS WELL AS THE PROMISING RESULTS OF ONGOING RESEARCH IN THE FIELD OF EPIGENETIC DRUGS THAT COULD REPRESENT ADDITIONAL OPTIONS IN OUR THERAPEUTIC ARMAMENTARIUM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE. 2011 10 4216 41 METHYL DONOR MICRONUTRIENTS: A POTENTIAL DIETARY EPIGENETIC TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY AN ABERRANT IMMUNE RESPONSE AND PERSISTENT INFLAMMATION. ITS PATHOGENESIS REMAINS UNKNOWN; HOWEVER, A COMPLEX INTERACTION BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN SUGGESTED TO CAUSE DISEASE ONSET. SEVERAL STUDIES HAVE DEMONSTRATED THAT EPIGENETIC ALTERATIONS, SUCH AS DNA HYPOMETHYLATION, MIRNA OVEREXPRESSION, AND ALTERED HISTONE ACETYLATION, MAY CONTRIBUTE TO SLE ONSET AND THE DISEASE'S CLINICAL MANIFESTATIONS. EPIGENETIC CHANGES, ESPECIALLY METHYLATION PATTERNS, ARE MODIFIABLE AND SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS DIET. IT IS WELL KNOWN THAT METHYL DONOR NUTRIENTS, SUCH AS FOLATE, METHIONINE, CHOLINE, AND SOME B VITAMINS, PLAY A RELEVANT ROLE IN DNA METHYLATION BY PARTICIPATING AS METHYL DONORS OR COENZYMES IN ONE-CARBON METABOLISM. BASED ON THIS KNOWLEDGE, THIS CRITICAL LITERATURE REVIEW AIMED TO INTEGRATE THE EVIDENCE IN ANIMAL MODELS AND HUMANS REGARDING THE ROLE OF NUTRIENTS IN EPIGENETIC HOMEOSTASIS AND THEIR IMPACT ON IMMUNE SYSTEM REGULATION TO SUGGEST A POTENTIAL EPIGENETIC DIET THAT COULD SERVE AS ADJUVANT THERAPY IN SLE. 2023 11 1604 30 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 12 607 36 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011 13 2524 42 EPIGENETICS AND THE UREMIC PHENOTYPE: A MATTER OF BALANCE. EPIGENETICS, WHICH IS THE STUDY OF CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN DNA SEQUENCE, IS A NOVEL DISCIPLINE THAT HAS LANGUISHED IN THE SHADOW OF ITS GENOMIC BIG BROTHER. SO FAR, STUDIES OF THE EPIGENOME HAVE ATTRACTED LITTLE INTEREST IN NEPHROLOGY. CHRONIC KIDNEY DISEASE IS AN EXAMPLE OF COMPLEX DISEASE IN WHICH THE PHENOTYPE ARISES FROM A COMBINATION OF ENVIRONMENTAL AND HERITABLE FACTORS. EVIDENCE SUGGESTS THAT THE CONTRIBUTION MADE BY THE ENVIRONMENT MAY BE MEDIATED VIA MODIFICATIONS OF THE EPIGENOME. IN THE UREMIC MILIEU, SEVERAL FEATURES SUCH AS INFLAMMATION, DYSLIPIDEMIA, HYPERHOMOCYSTEINEMA, OXIDATIVE STRESS AS WELL AS VITAMIN AND NUTRITIONAL DEFICIENCIES MAY AFFECT ABERRANT GLOBAL DNA METHYLATION. HOWEVER, AS HYPERHOMOCYSTEINEMIA SEEMS TO PROMOTE GLOBAL DNA HYPOMETHYLATION AND PERSISTENT INFLAMMATION DNA HYPERMETHYLATION, THE EFFECTS OF THE UREMIC MILIEU ON ABERRANT GLOBAL DNA METHYLATION MAY BE COMPLEX AND CONTEXT-SENSITIVE. IT SHOULD BE EMPHASIZED THAT IN ANALOGY TO THE UNSPECIFIC NATURE OF FEVER, ABERRANT GLOBAL DNA METHYLATION IS ONLY A SIGN OF A GENERALIZED EPIGENETIC DYSREGULATION. THUS, TO PROVIDE BETTER UNDERSTANDING OF THE EFFECTS OF ABERRANT DNA METHYLATION ON THE UREMIC PHENOTYPE, FURTHER STUDIES EVALUATING SITE-SPECIFIC INFORMATION ON METHYLATION IN VARIOUS CANDIDATE GENES ARE NEEDED. THE SCIENCE OF EPIGENETICS MAY NOT ONLY UNCOVER ETIOLOGIC AND PATHOGENIC MECHANISMS IN UREMIA, BUT MAY ALSO BE OF HELP TO DEVELOP NOVEL TREATMENT STRATEGIES TARGETING THE UNACCEPTABLE HIGH DEATH RISK IN CARDIOVASCULAR COMPLICATIONS IN THIS PATIENT POPULATION. 2008 14 6113 29 THE EPIGENETIC CONDUCTOR: A GENOMIC ORCHESTRATOR IN CHRONIC KIDNEY DISEASE COMPLICATIONS? EPIGENETICS DEFINES THE CELLULARLY HERITABLE PROPERTIES OF GENOME FUNCTION, WHICH ARE NOT DIRECTLY ENCODED IN THE DNA PRIMARY SEQUENCE. THE UNDERLYING MECHANISMS ORCHESTRATE CELL IDENTITY AND MEMORY AND ARE TARGETS FOR EXTERNAL AND INTERNAL ENVIRONMENTAL INFLUENCES. IT BECOMES INCREASINGLY CLEAR THAT GENETIC AND EPIGENETIC FACTORS ARE COMPLETELY INTERDEPENDENT FOR HOMEOSTASIS. SUBSEQUENTLY, THE SAME IS CERTAINLY TRUE FOR DISEASE. OUR UNDERSTANDING OF EPIGENETIC MECHANISMS IN CHRONIC KIDNEY DISEASE (CKD) IS STILL LAGGING, AND FURTHER STUDIES ARE NEEDED TO UNDERSTAND THE IMPORTANCE OF, E.G., ABERRANT DNA METHYLATION IN RELATION TO THE UREMIC IMPACT ON THE FUNCTIONAL GENOME, ORGANISMAL METABOLISM AND ASSOCIATED PREMATURE VASCULAR DISEASE. MORE RESEARCH IN THIS FIELD WILL ALSO HELP US UNDERSTAND THE LINKS BETWEEN ALTERED GENE REGULATION OF SPECIFIC GENES BY THE UREMIC ENVIRONMENT VIA EPIGENETIC MECHANISMS, AND INITIATION AND PROGRESSION OF ATHEROSCLEROSIS. THE DYNAMIC NATURE OF EPIGENETIC MECHANISMS PROMPTS THERAPEUTIC INVESTIGATIONS IN CKD, TARGETING THE EPIGENOME WITH EPIGENETIC DRUGS. THE IMPORTANCE OF 1-CARBON METABOLISM FOR EPIGENETIC MODIFICATIONS SUGGESTS THAT SPECIFIC DIETS MAY ALSO PROVE TO PLAY AN IMPORTANT PART AS EFFICIENT REMEDIES IN CKD AND ASSOCIATED ATHEROSCLEROTIC PATHOLOGIES. 2009 15 5660 33 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 16 3438 44 HYPERHOMOCYSTEINEMIA IN UREMIA--A RED FLAG IN A DISRUPTED CIRCUIT. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ACCORDING TO MOST OBSERVATIONAL STUDIES AND TO STUDIES USING THE MENDELIAN RANDOMIZATION APPROACH, UTILIZING THE COMMON POLYMORPHISM C677T OF METHYLENE TETRAHYDROFOLATE REDUCTASE. IN CONTRAST, THE MOST RECENT SECONDARY PREVENTIVE INTERVENTION STUDIES, IN THE GENERAL POPULATION AND IN CHRONIC KIDNEY DISEASE (CKD) AND UREMIA, WHICH ARE ALL NEGATIVE (WITH THE POSSIBLE NOTABLE EXCEPTION OF STROKE), POINT TO OTHER DIRECTIONS. HOWEVER, ALL TRIALS USE FOLIC ACID IN VARIOUS DOSAGES AS A MEANS TO REDUCE HOMOCYSTEINE LEVELS, WITH THE ADDITION OF VITAMINS B6 AND B12. IT IS POSSIBLE THAT FOLIC ACID HAS NEGATIVE EFFECTS, WHICH OFFSET THE BENEFITS; ALTERNATIVELY, HOMOCYSTEINE COULD BE AN INNOCENT BY-STANDER, OR A SURROGATE OF THE REAL CULPRIT. THE LATTER POSSIBILITY LEADS US TO THE SEARCH FOR POTENTIAL CANDIDATES. FIRST, THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH BY ITSELF IS CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, SHOW. IN CKD AND IN UREMIA, HYPERHOMOCYSTEINEMIA AND HIGH INTRACELLULAR ADOHCY ARE PRESENT AND ARE ASSOCIATED WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION, SUCH AS IMPRINTED GENES, AND PSEUDOAUTOSOMAL GENES, THUS POINTING TO EPIGENETIC DYSREGULATION. THESE ALTERATIONS ARE SUSCEPTIBLE TO REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. SECOND, IT HAS TO BE KEPT IN MIND THAT HOMOCYSTEINE IS MAINLY PROTEIN-BOUND, AND ITS EFFECTS COULD BE LINKED THEREFORE TO PROTEIN HOMOCYSTEINYLATION. IN THIS RESPECT, INCREASED PROTEIN HOMOCYSTEINYLATION HAS BEEN FOUND IN UREMIA, LEADING TO ALTERATIONS IN PROTEIN FUNCTION. 2009 17 2982 33 GENETIC CONSIDERATIONS IN PEDIATRIC CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IN CHILDREN IS AN IRREVERSIBLE PROCESS THAT, IN SOME CASES, MAY LEAD TO END-STAGE RENAL DISEASE. THE MAJORITY OF CHILDREN WITH CKD HAVE A CONGENITAL DISORDER OF THE KIDNEY OR UROLOGICAL TRACT ARISING FROM BIRTH. THERE IS STRONG EVIDENCE FOR BOTH A GENETIC AND EPIGENETIC COMPONENT TO PROGRESSION OF CKD. UTILIZATION OF GENE-MAPPING STRATEGIES, RANGING FROM GENOME-WIDE ASSOCIATION STUDIES TO SINGLE-NUCLEOTIDE POLYMORPHISM ANALYSIS, SERVES TO IDENTIFY POTENTIAL GENETIC VARIANTS THAT MAY LEND TO DISEASE VARIATION. GENOME-WIDE ASSOCIATION STUDIES EVALUATING POPULATION-BASED DATA HAVE IDENTIFIED DIFFERENT LOCI ASSOCIATED WITH CKD PROGRESSION. ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ON AN INDIVIDUAL LEVEL SUGGESTS THAT SECONDARY SYSTEMIC SEQUELAE OF CKD ARE CLOSELY RELATED TO DYSFUNCTION OF THE CARDIOVASCULAR-INFLAMMATORY AXIS AND MAY LEAD TO ADVANCED CARDIOVASCULAR DISEASE THROUGH ABNORMAL VASCULAR CALCIFICATION AND ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM. SIMILARLY, GENETIC VARIANTS AFFECTING CYTOKINE CONTROL, FIBROSIS, AND PARENCHYMAL DEVELOPMENT MAY MODULATE CKD THROUGH DEVELOPMENT AND ACCELERATION OF RENAL INTERSTITIAL FIBROSIS. EPIGENETIC STUDIES EVALUATE MODIFICATION OF THE GENOME THROUGH DNA METHYLATION, HISTONE MODIFICATION, OR RNA INTERFERENCE, WHICH MAY BE DIRECTLY INFLUENCED BY EXTERNAL OR ENVIRONMENTAL FACTORS DIRECTING GENOMIC EXPRESSION. LASTLY, IMPROVED UNDERSTANDING OF THE GENETIC AND EPIGENETIC CONTRIBUTION TO CKD PROGRESSION MAY ALLOW PROVIDERS TO IDENTIFY A POPULATION AT ACCELERATED RISK FOR DISEASE PROGRESSION AND APPLY NOVEL THERAPIES TARGETED AT THE GENETIC MECHANISM OF DISEASE. 2016 18 6725 33 VITAMIN D: NOT JUST BONE METABOLISM BUT A KEY PLAYER IN CARDIOVASCULAR DISEASES. VITAMIN D IS THE FIRST ITEM OF DRUG EXPENDITURE FOR THE TREATMENT OF OSTEOPOROSIS. ITS DEFICIENCY IS A CONDITION THAT AFFECTS NOT ONLY OLDER INDIVIDUALS BUT ALSO YOUNG PEOPLE. RECENTLY, THE SCIENTIFIC COMMUNITY HAS FOCUSED ITS ATTENTION ON THE POSSIBLE ROLE OF VITAMIN D IN THE DEVELOPMENT OF SEVERAL CHRONIC DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISEASES. THIS REVIEW AIMS TO HIGHLIGHT THE POSSIBLE ROLE OF VITAMIN D IN CARDIOVASCULAR AND METABOLIC DISEASES. IN PARTICULAR, HERE WE EXAMINE (1) THE ROLE OF VITAMIN D IN DIABETES MELLITUS, METABOLIC SYNDROME, AND OBESITY, AND ITS INFLUENCE ON INSULIN SECRETION; (2) ITS ROLE IN ATHEROSCLEROSIS, IN WHICH CHRONIC VITAMIN D DEFICIENCY, LOWER THAN 20 NG/ML (50 NMOL/L), HAS EMERGED AMONG THE NEW RISK FACTORS; (3) THE ROLE OF VITAMIN D IN ESSENTIAL HYPERTENSION, IN WHICH LOW PLASMA LEVELS OF VITAMIN D HAVE BEEN ASSOCIATED WITH BOTH AN INCREASE IN THE PREVALENCE OF HYPERTENSION AND DIASTOLIC HYPERTENSION; (4) THE ROLE OF VITAMIN D IN PERIPHERAL ARTERIOPATHIES AND ANEURYSMAL PATHOLOGY, REPORTING THAT PATIENTS WITH PERIPHERAL ARTERY DISEASES HAD LOWER VITAMIN D VALUES THAN NON-SUFFERING PAD CONTROLS; (5) THE GENETIC AND EPIGENETIC ROLE OF VITAMIN D, HIGHLIGHTING ITS TRANSCRIPTIONAL REGULATION CAPACITY; AND (6) THE ROLE OF VITAMIN D IN CARDIAC REMODELING AND DISEASE. DESPITE THE MANY OBSERVATIONAL STUDIES AND META-ANALYSES SUPPORTING THE CRITICAL ROLE OF VITAMIN D IN CARDIOVASCULAR PHYSIOPATHOLOGY, CLINICAL TRIALS DESIGNED TO EVALUATE THE SPECIFIC ROLE OF VITAMIN D IN CARDIOVASCULAR DISEASE ARE SCARCE. THE CHARACTERIZATION OF THE IMPORTANCE OF VITAMIN D AS A MARKER OF PATHOLOGY SHOULD REPRESENT A FUTURE RESEARCH CHALLENGE. 2021 19 2609 34 EPIGENETICS: A POTENTIAL KEY MECHANISM INVOLVED IN THE PATHOGENESIS OF CARDIORENAL SYNDROMES. EPIGENETICS IS DEFINED AS THE HERITABLE CHANGES IN GENE EXPRESSION PATTERNS WHICH ARE NOT DIRECTLY ENCODED BY MODIFICATIONS IN THE NUCLEOTIDE DNA SEQUENCE OF THE GENOME, INCLUDING HIGHER ORDER CHROMATIN ORGANIZATION, DNA METHYLATION, CYTOSINE MODIFICATIONS, COVALENT HISTONE TAIL MODIFICATIONS, AND SHORT NON-CODING RNA MOLECULES. RECENTLY, MUCH ATTENTION HAS BEEN PAID TO THE ROLE AND THE FUNCTION OF EPIGENETICS AND EPIMUTATIONS IN THE CELLULAR AND SUBCELLULAR PATHWAYS AND IN THE REGULATION OF GENES IN THE SETTING OF BOTH KIDNEY AND CARDIOVASCULAR DISEASE. INDEED, DEREGULATION OF HISTONE ALTERATIONS HAS BEEN HIGHLIGHTED IN A LARGE SPECTRUM OF RENAL AND CARDIAC DISEASE, INCLUDING CHRONIC AND ACUTE RENAL INJURY, RENAL AND CARDIAC FIBROSIS, CARDIAC HYPERTROPHY AND FAILURE, KIDNEY CONGENITAL ANOMALIES, RENAL HYPOXIA, AND DIABETIC RENAL COMPLICATIONS. NEVERTHELESS, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF CARDIORENAL SYNDROMES IS CURRENTLY UNDEREXPLORED. GIVEN THE SIGNIFICANT CLINICAL RELEVANCE OF HEART-KIDNEY CROSSTALK, EFFORTS IN THE RESEARCH FOR NEW ACTION MECHANISMS CONCURRENTLY OPERATING IN BOTH PATHOLOGIES ARE THUS OF MAXIMUM INTEREST. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN HEART AND KIDNEY DISEASE, AND THEIR POSSIBLE ROLE IN THE SETTING OF CARDIORENAL SYNDROMES. 2018 20 2360 23 EPIGENETIC REGULATION OF SKELETAL MUSCLE METABOLISM. NORMAL SKELETAL MUSCLE METABOLISM IS ESSENTIAL FOR WHOLE BODY METABOLIC HOMOEOSTASIS AND DISRUPTIONS IN MUSCLE METABOLISM ARE ASSOCIATED WITH A NUMBER OF CHRONIC DISEASES. TRANSCRIPTIONAL CONTROL OF METABOLIC ENZYME EXPRESSION IS A MAJOR REGULATORY MECHANISM FOR MUSCLE METABOLIC PROCESSES. SUBSTANTIAL EVIDENCE IS EMERGING THAT HIGHLIGHTS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN THIS PROCESS. THIS REVIEW WILL EXAMINE THE IMPORTANCE OF EPIGENETICS IN THE REGULATION OF MUSCLE METABOLISM, WITH A PARTICULAR EMPHASIS ON DNA METHYLATION AND HISTONE ACETYLATION AS EPIGENETIC CONTROL POINTS. THE EMERGING CROSS-TALK BETWEEN METABOLISM AND EPIGENETICS IN THE CONTEXT OF HEALTH AND DISEASE WILL ALSO BE EXAMINED. THE CONCEPT OF INHERITANCE OF SKELETAL MUSCLE METABOLIC PHENOTYPES WILL BE DISCUSSED, IN ADDITION TO EMERGING EPIGENETIC THERAPIES THAT COULD BE USED TO ALTER MUSCLE METABOLISM IN CHRONIC DISEASE STATES. 2016