1 6129 133 THE EPIGENETIC REGULATION OF PODOCYTE FUNCTION IN DIABETES. CHRONIC HYPERGLYCEMIA EARLY IN THE COURSE OF DIABETES CONFERS A SUSTAINED INCREASE IN THE RISK OF COMPLICATIONS DEVELOPMENT. IN RECENT YEARS, EFFORTS TO UNDERSTAND THE MOLECULAR BASIS FOR THIS "METABOLIC MEMORY" HAVE FOCUSED ON EPIGENETIC MECHANISMS AS A MEANS BY WHICH TRANSIENT HIGH GLUCOSE CAN CAUSE PERSISTENT AND PROPAGATED CHANGES IN CELL FUNCTION. FOR INSTANCE, IN VASCULAR ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS AND PERIPHERAL BLOOD CELLS, TEMPORARY EXPOSURE TO HIGH GLUCOSE CAUSES CHANGES IN EPIGENETIC MARKS THAT PROMOTE A SHIFT TOWARDS A PRO-INFLAMMATORY PHENOTYPE. HOWEVER, THE INFLUENCE OF EPIGENETIC PROCESSES IN COMPLICATIONS DEVELOPMENT EXTENDS BEYOND THEIR CONTRIBUTION TO METABOLIC MEMORY. PODOCYTES, FOR EXAMPLE, ARE TERMINALLY DIFFERENTIATED CELLS OF THE RENAL GLOMERULUS WHOSE INJURY IS A MAJOR CONTRIBUTOR TO THE PATHOGENESIS OF NEPHROPATHY. OVER RECENT MONTHS, SEVERAL REPORTS HAVE EMERGED DESCRIBING THE ESSENTIAL ACTIONS OF HISTONE-MODIFYING ENZYMES AND DNA METHYLATION PATTERNS (THE TWO PRINCIPAL EPIGENETIC MECHANISMS) IN MAINTAINING PODOCYTE INTEGRITY, ESPECIALLY UNDER DIABETIC CONDITIONS. HERE, WE REVIEW THE KNOWN AND POTENTIAL ROLE OF EPIGENETIC PROCESSES WITHIN PODOCYTES, FOCUSING ON THE EVIDENCE LINKING THESE PROCESSES TO OXIDATIVE STRESS, CROSSTALK WITH TUBULE CELLS, AUTOPHAGY AND SLIT-PORE PROTEIN EXPRESSION. WHETHER PODOCYTES THEMSELVES EXHIBIT A METABOLIC MEMORY AWAITS TO BE SEEN. 2015 2 1487 33 DNA DAMAGE AND EPIGENETIC CHANGES IN KIDNEY DISEASES - FOCUSED ON TRANSCRIPTION FACTORS IN PODOCYTES. RECENTLY IT HAS BEEN SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF CARIDIOVASCULAR AND METABOLIC DISEASES, INCLUDING DIABETES, OBESITY, ATHEROSCLEROSIS, HEART FAILURE, HYPERTENSION AND KIDNEY DISEASES. IN THESE CHRONIC DISEASES, VARIOUS EXOGENOUS AND ENDOGENOUS STRESSES CAUSE DNA DAMAGE, FOLLOWED BY DNA REPAIR PROCESS. ACCUMULATION OF DNA DAMAGES AND IMPAIRED REPAIR PROCESS CAN LEAD TO EPIGENETIC CHANGES, WHICH MAY CONTRIBUTE TO ONSET AND PROGRESSION OF DISEASES. RECENTLY WE HAVE SHOWN THAT THERAPEUTIC EFFECT OF TRANSCRIPTION FACTOR KLF4 (KRUPPEL-LIKE FACTOR 4) IN KIDNEY GLOMERULAR EPITHELIAL CELLS (PODOCYTES) ON PROTEINURIC KIDNEY DISEASES THROUGH EPIGENETIC MECHANISMS. OUR RESULT SUGGESTS THE POSSIBILITY OF TRANSCRIPTION FACTORS AS A TARGET OF SELECTIVE EPIGENETIC THERAPY. MOREOVER, WE HAVE REPORTED THAT RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKERS, WHICH ARE WIDELY PRESCRIBED FOR THE TREATMENT OF CARDIOVASCULAR DISEASES, CAN RESTORE EPIGENETIC CHANGES THROUGH KLF4 IN PART. THESE RESULTS SUGGEST THAT ACTIVATION OF RAS CAUSES EPIGENETIC CHANGES IN DISEASE STATES, AND ELUCIDATION OF THE PRECISE MECHANISM MAY LEAD TO ESTABLISHMENT OF NOVEL THERAPEUTIC TARGET OF KIDNEY DISEASES. IN THIS REVIEW WE FOCUS ON DNA DAMAGE REPAIR SYSTEM AND EPIGENETIC MODULATORS IN DISEASE STATES, AND SPECULATE A CANDIDATE FOR EPIGENETIC THERAPY OF KIDNEY DISEASES. 2016 3 3156 42 GLYCEMIC MEMORIES AND THE EPIGENETIC COMPONENT OF DIABETIC NEPHROPATHY. A STRONG CASE FOR THE DEREGULATION OF EPIGENETIC CHROMATIN MODIFICATIONS IN THE DEVELOPMENT AND PROGRESSION OF VARIOUS CHRONIC COMPLICATIONS OF DIABETES HAS EMERGED FROM RECENT EXPERIMENTAL OBSERVATIONS. CLINICAL TRIALS OF TYPE 1 AND TYPE 2 DIABETES PATIENTS HIGHLIGHT THE IMPORTANCE OF EARLY AND INTENSIVE TREATMENT AND THE PROLONGED DAMAGE OF HYPERGLYCEMIA ON ORGANS SUCH AS THE KIDNEY. THE FUNCTIONAL RELATIONSHIP BETWEEN THE REGULATION OF CHROMATIN ARCHITECTURE AND PERSISTENT GENE EXPRESSION CHANGES CONFERRED BY PRIOR HYPERGLYCEMIA REPRESENTS AN IMPORTANT AVENUE OF INVESTIGATION FOR EXPLAINING DIABETIC NEPHROPATHY. WHILE SEVERAL STUDIES IMPLICATE EPIGENETIC CHANGES AT THE CHROMATIN TEMPLATE IN THE DEREGULATED GENE EXPRESSION ASSOCIATED WITH DIABETIC NEPHROPATHY, THE MOLECULAR DETERMINANTS OF METABOLIC MEMORY IN RENAL CELLS REMAIN POORLY UNDERSTOOD. THERE IS NOW STRONG EVIDENCE FROM EXPERIMENTAL ANIMALS AND CELL CULTURE OF PERSISTENT GLUCOSE-DRIVEN CHANGES IN VASCULAR ENDOTHELIAL GENE EXPRESSION THAT MAY ALSO HAVE RELEVANCE FOR THE MICROVASCULATURE OF THE KIDNEY. EXPLORATION OF EPIGENETIC MECHANISMS UNDERLYING THE HYPERGLYCEMIC CUE MEDIATING PERSISTENT TRANSCRIPTIONAL CHANGES IN RENAL CELLS HOLDS NOVEL THERAPEUTIC POTENTIAL FOR DIABETIC NEPHROPATHY. 2013 4 2613 45 EPIGENETICS: DECIPHERING ITS ROLE IN DIABETES AND ITS CHRONIC COMPLICATIONS. 1. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS MIGHT REGULATE THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT, AND AFFECT HUMAN DISEASES, SUCH AS DIABETES AND ITS COMPLICATIONS. 2. CLINICAL TRIALS HAVE UNDERSCORED THE LONG LASTING BENEFICIAL EFFECTS OF STRICT GLYCAEMIC CONTROL FOR REDUCING THE PROGRESSION OF DIABETIC COMPLICATIONS. THEY HAVE ALSO SHOWN THAT DIABETIC COMPLICATIONS, SUCH AS DIABETIC NEPHROPATHY, A CHRONIC KIDNEY DISORDER, CAN CONTINUE EVEN AFTER BLOOD GLUCOSE NORMALIZATION, SUGGESTING A METABOLIC MEMORY OF THE PRIOR GLYCAEMIC STATE. 3. DYSREGULATION OF EPIGENETIC POST-TRANSCRIPTIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, INCLUDING HISTONE LYSINE METHYLATION, HAS BEEN IMPLICATED IN ABERRANT GENE REGULATION ASSOCIATED WITH THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS. GENOME-WIDE STUDIES HAVE SHOWN CELL-TYPE SPECIFIC CHANGES IN HISTONE METHYLATION PATTERNS UNDER DIABETIC CONDITIONS. IN ADDITION, STUDIES IN VASCULAR CELLS HAVE SHOWN LONG LASTING CHANGES IN EPIGENETIC MODIFICATIONS AT KEY INFLAMMATORY GENE PROMOTERS AFTER PRIOR EXPOSURE TO DIABETIC CONDITIONS, SUGGESTING A POSSIBLE MECHANISM FOR METABOLIC MEMORY. 4. RECENT STUDIES HAVE SHOWN ROLES FOR HISTONE METHYLATION, DNA METHYLATION, AS WELL AS MICRORNA IN DIABETIC NEPHROPATHY. WHETHER THESE EPIGENETIC FACTORS PLAY A ROLE IN METABOLIC MEMORY OF DIABETIC KIDNEY DISEASE IS LESS WELL UNDERSTOOD. 5. THE INCIDENCE OF DIABETES IS GROWING RAPIDLY, AS ALSO THE COST OF TREATING THE RESULTING COMPLICATIONS. A BETTER UNDERSTANDING OF METABOLIC MEMORY AND THE POTENTIAL INVOLVEMENT OF EPIGENETIC MECHANISMS IN THIS PHENOMENON COULD ENABLE THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS FOR THE TREATMENT AND/OR PREVENTION OF SUSTAINED DIABETIC COMPLICATIONS. 2011 5 607 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 6 859 34 CHROMATIN DYNAMICS IN KIDNEY DEVELOPMENT AND FUNCTION. EPIGENETIC MECHANISMS ARE FUNDAMENTAL KEY FEATURES OF DEVELOPING CELLS CONNECTING DEVELOPMENTAL REGULATORY FACTORS TO CHROMATIN MODIFICATION. CHANGES IN THE ENVIRONMENT DURING RENAL DEVELOPMENT CAN HAVE LONG-LASTING EFFECTS ON THE PERMANENT TISSUE STRUCTURE AND THE LEVEL OF EXPRESSION OF IMPORTANT FUNCTIONAL GENES. THESE CHANGES ARE BELIEVED TO CONTRIBUTE TO KIDNEY DISEASE OCCURRENCE AND PROGRESSION. ALTHOUGH THE MECHANISMS OF EARLY PATTERNING AND CELL FATE HAVE BEEN WELL DESCRIBED FOR RENAL DEVELOPMENT, LITTLE IS KNOWN ABOUT ASSOCIATED EPIGENETIC MODIFICATIONS AND THEIR IMPACT ON HOW GENES INTERACT TO SPECIFY THE RENAL EPITHELIAL CELLS OF NEPHRONS AND HOW THIS SPECIFICATION IS RELEVANT TO MAINTAINING NORMAL RENAL FUNCTION. A BETTER UNDERSTANDING OF THE RENAL CELL-SPECIFIC EPIGENETIC MODIFICATIONS AND THE INTERACTION OF DIFFERENT CELL TYPES TO FORM THIS HIGHLY COMPLEX ORGAN WILL NOT ONLY HELP TO BETTER UNDERSTAND DEVELOPMENTAL DEFECTS AND EARLY LOSS OF KIDNEY FUNCTION IN CHILDREN, BUT ALSO HELP TO UNDERSTAND AND IMPROVE CHRONIC DISEASE PROGRESSION, CELL REGENERATION AND RENAL AGING. 2014 7 6638 54 UNRAVELING THE EPIGENETIC LANDSCAPE OF GLOMERULAR CELLS IN KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A MAJOR PUBLIC HEALTH CONCERN AND ITS PREVALENCE AND INCIDENCE ARE RISING QUICKLY. IT IS A NON-COMMUNICABLE DISEASE PRIMARILY CAUSED BY DIABETES AND/OR HYPERTENSION AND IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. DESPITE DECADES OF RESEARCH EFFORTS, THE PATHOGENESIS OF CKD REMAINS A PUZZLE WITH MISSING PIECES. UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS THAT GOVERN THE LOSS OF KIDNEY FUNCTION IS CRUCIAL. ABRUPT REGULATION OF GENE EXPRESSION IN KIDNEY CELLS IS APPARENT IN CKD AND SHOWN TO BE RESPONSIBLE FOR DISEASE ONSET AND PROGRESSION. GENE EXPRESSION REGULATION EXTENDS BEYOND DNA SEQUENCE AND INVOLVES EPIGENETIC MECHANISMS INCLUDING CHANGES IN DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, DRIVEN BY THE ACTIVITY OF SPECIFIC ENZYMES. RECENT ADVANCES DEMONSTRATE THE ESSENTIAL PARTICIPATION OF EPIGENETICS IN KIDNEY (PATHO)PHYSIOLOGY, AS ITS ACTIONS REGULATE BOTH THE INTEGRITY OF CELLS BUT ALSO TRIGGERS DELETERIOUS SIGNALING PATHWAYS. HERE, WE REVIEW THE KNOWN EPIGENETIC PROCESSES REGULATING THE COMPLEX FILTRATION UNIT OF THE KIDNEY, THE GLOMERULI. THE REVIEW WILL ELABORATE ON NOVEL INSIGHTS INTO HOW EPIGENETICS CONTRIBUTES TO CELL INJURY IN THE CKD SETTING MAJORLY FOCUSING ON KIDNEY GLOMERULAR CELLS: THE GLOMERULAR ENDOTHELIAL CELLS, THE MESANGIAL CELLS, AND THE SPECIALIZED AND TERMINALLY DIFFERENTIATED PODOCYTE CELLS. 2021 8 5923 41 TARGETING DNA METHYLATION IN PODOCYTES TO OVERCOME CHRONIC KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS ON THE RISE WORLDWIDE, AND THERE IS URGENT NEED FOR THE DEVELOPMENT OF EFFECTIVE PLANS AGAINST THE INCREASING INCIDENCE OF CKD. PODOCYTES, GLOMERULAR EPITHELIAL CELLS, ARE AN INTEGRAL PART OF THE PRIMARY FILTRATION UNIT OF THE KIDNEY AND FORM A SLIT MEMBRANE AS A BARRIER TO PREVENT PROTEINURIA. THE ROLE OF PODOCYTES IN THE PATHOGENESIS AND PROGRESSION OF CKD IS NOW RECOGNIZED. PODOCYTE FUNCTION DEPENDS ON A SPECIALIZED MORPHOLOGY WITH THE ARRANGED FOOT PROCESSES, WHICH IS DIRECTLY RELATED TO THEIR FUNCTION. EPIGENETIC CHANGES RESPONSIBLE FOR THE REGULATION OF GENE EXPRESSION RELATED TO PODOCYTE MORPHOLOGY HAVE BEEN SHOWN TO BE IMPORTANT IN THE PATHOGENESIS OF CKD. ALTHOUGH EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA-BASED REGULATION, WE HAVE FOCUSED ON DNA METHYLATION CHANGES BECAUSE THEY ARE MORE STABLE THAN OTHER EPIGENETIC MODIFICATIONS. THIS REVIEW SUMMARIZES RECENT LITERATURE ABOUT THE ROLE OF ALTERED DNA METHYLATION IN THE KIDNEY, ESPECIALLY IN GLOMERULAR PODOCYTES, FOCUSING ON TRANSCRIPTION FACTORS AND DNA DAMAGE RESPONSES THAT ARE CLOSELY ASSOCIATED WITH THE FORMATION OF DNA METHYLATION CHANGES. 2023 9 2195 35 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 10 347 49 ALTERED DNA METHYLATION IN KIDNEY DISEASE: USEFUL MARKERS AND THERAPEUTIC TARGETS. RECENT STUDIES HAVE DEMONSTRATED THE ASSOCIATION OF ALTERED EPIGENOMES WITH LIFESTYLE-RELATED DISEASES. EPIGENETIC REGULATION PROMOTES BIOLOGICAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL CHANGES, AND SUCH PLASTICITY MAY CAUSE A 'MEMORY EFFECT', A SUSTAINED EFFECT OF TRANSIENT TREATMENT OR AN INSULT IN THE COURSE OF LIFESTYLE-RELATED DISEASES. WE INVESTIGATED THE SIGNIFICANCE OF EPIGENETIC CHANGES IN SEVERAL GENES REQUIRED FOR RENAL INTEGRITY, INCLUDING THE NEPHRIN GENE IN PODOCYTES, AND THE SUSTAINED ANTI-PROTEINURIC EFFECT, FOCUSING ON THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4). WE FURTHER REPORTED THE ROLE OF THE DNA REPAIR FACTOR LYSINE-ACETYL TRANSFERASE 5 (KAT5), WHICH ACTS COORDINATELY WITH KLF4, IN PODOCYTE INJURY CAUSED BY A HYPERGLYCEMIC STATE THROUGH THE ACCELERATION OF DNA DAMAGE AND EPIGENETIC ALTERATION. IN CONTRAST, KAT5 IN PROXIMAL TUBULAR CELLS PREVENTS ACUTE KIDNEY INJURY VIA GLOMERULAR FILTRATION REGULATION BY AN EPIGENETIC MECHANISM AS WELL AS PROMOTION OF DNA REPAIR, INDICATING THE CELL TYPE-SPECIFIC ACTION AND ROLES OF DNA REPAIR FACTORS. THIS REVIEW SUMMARIZES EPIGENETIC ALTERATIONS IN KIDNEY DISEASES, ESPECIALLY DNA METHYLATION, AND THEIR UTILITY AS MARKERS AND POTENTIAL THERAPEUTIC TARGETS. FOCUSING ON TRANSCRIPTION FACTORS OR DNA DAMAGE REPAIR FACTORS ASSOCIATED WITH EPIGENETIC CHANGES MAY BE MEANINGFUL DUE TO THEIR CELL-SPECIFIC EXPRESSION OR ACTION. WE BELIEVE THAT A BETTER UNDERSTANDING OF EPIGENETIC ALTERATIONS IN THE KIDNEY WILL LEAD TO THE DEVELOPMENT OF A NOVEL STRATEGY FOR CHRONIC KIDNEY DISEASE (CKD) TREATMENT. 2022 11 2163 38 EPIGENETIC MECHANISMS IN DIABETIC VASCULAR COMPLICATIONS. THERE HAS BEEN A RAPID INCREASE IN THE INCIDENCE OF DIABETES AS WELL THE ASSOCIATED VASCULAR COMPLICATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN IMPLICATED IN THESE PATHOLOGIES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. ACTIONS OF MAJOR PATHOLOGICAL MEDIATORS OF DIABETES AND ITS COMPLICATIONS SUCH AS HYPERGLYCAEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS CAN LEAD TO DYSREGULATED EPIGENETIC MECHANISMS THAT AFFECT CHROMATIN STRUCTURE AND GENE EXPRESSION. FURTHERMORE, PERSISTENCE OF THIS ALTERED STATE OF THE EPIGENOME MAY BE THE UNDERLYING MECHANISM CONTRIBUTING TO A 'METABOLIC MEMORY' THAT RESULTS IN CHRONIC INFLAMMATION AND VASCULAR DYSFUNCTION IN DIABETES EVEN AFTER ACHIEVING GLYCAEMIC CONTROL. FURTHER EXAMINATION OF EPIGENETIC MECHANISMS BY ALSO TAKING ADVANTAGE OF RECENTLY DEVELOPED NEXT-GENERATION SEQUENCING TECHNOLOGIES CAN PROVIDE NOVEL INSIGHTS INTO THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS AND LEAD TO THE DISCOVERY OF MUCH NEEDED NEW DRUG TARGETS FOR THESE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF EPIGENETICS IN DIABETES AND ITS VASCULAR COMPLICATIONS, AND RECENT TECHNOLOGICAL ADVANCES THAT HAVE SIGNIFICANTLY ACCELERATED THE FIELD. 2011 12 3826 42 INVESTIGATION OF EPIGENETICS IN KIDNEY CELL BIOLOGY. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN DNA OR ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN THE PROCESSES OF KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATIONS VIA EPIGENETIC REGULATORS AND INTERACTION VIA TRANSCRIPTION FACTORS, AND NONCODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, NEPHRITIC AND NEPHROTIC SYNDROMES, PYELONEPHRITIS AND POLYCYSTIC KIDNEY DISEASES ARE DRIVEN BY ABERRANT ACTIVITY IN NUMEROUS SIGNALING PATHWAYS IN EVEN INDIVIDUAL KIDNEY CELL. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, NONCODING RNAS, AND PROTEIN POSTTRANSLATIONAL MODIFICATIONS, COULD DISRUPT ESSENTIAL PATHWAYS THAT PROTECT THE RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND ESTABLISHMENT OF OTHER RENAL ASSOCIATED SYNDROMES, WHICH HAVE BEEN RECOGNIZED AS ONE OF THE CRITICAL MECHANISMS FOR REGULATING FUNCTIONAL CHANGES THAT DRIVE AND MAINTAIN THE KIDNEY DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE THE EPIGENETIC MECHANISMS IN KIDNEY CELL BIOLOGY AND EPIGENETIC BASIS OF KIDNEY DEVELOPMENT, AND INTRODUCE EPIGENETIC TECHNIQUES THAT CAN BE USED IN INVESTIGATING THE MOLECULAR MECHANISM OF KIDNEY CELL BIOLOGY AND KIDNEYS DISEASES, PRIMARILY FOCUSING ON THE INTEGRATION OF DNA METHYLATION AND CHROMATIN IMMUNOPRECIPITATION TECHNOLOGIES INTO KIDNEY DISEASE ASSOCIATED STUDIES. FUTURE STUDIES USING THESE EMERGING TECHNOLOGIES WILL ELUCIDATE HOW ALTERATIONS IN THE RENAL CELL EPIGENOME COOPERATE WITH GENETIC ABERRATIONS FOR KIDNEY DISEASE INITIATION AND PROGRESSION. INCORPORATING EPIGENOMIC TESTING INTO THE CLINICAL RESEARCH IS ESSENTIAL TO FUTURE STUDIES WITH EPIGENETICS BIOMARKERS AND PRECISION MEDICINE USING EMERGING EPIGENETIC THERAPIES. 2019 13 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 14 6510 33 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS. 2015 15 1604 34 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 16 1505 36 DNA METHYLATION AND HISTONE MODIFICATION IN HYPERTENSION. SYSTEMIC HYPERTENSION, WHICH EVENTUALLY RESULTS IN HEART FAILURE, RENAL FAILURE OR STROKE, IS A COMMON CHRONIC HUMAN DISORDER THAT PARTICULARLY AFFECTS ELDERS. ALTHOUGH MANY SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF HYPERTENSION HAVE BEEN REPORTED OVER THE PAST DECADES, WHICH HAS LED TO THE IMPLEMENTATION OF A WIDE VARIETY OF ANTI-HYPERTENSIVE THERAPIES, ONE HALF OF ALL HYPERTENSIVE PATIENTS STILL DO NOT HAVE THEIR BLOOD PRESSURE CONTROLLED. THE FRONTIER IN UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING HYPERTENSION HAS NOW ADVANCED TO THE LEVEL OF EPIGENOMICS. PARTICULARLY, INCREASING EVIDENCE IS EMERGING THAT DNA METHYLATION AND HISTONE MODIFICATIONS PLAY AN IMPORTANT ROLE IN GENE REGULATION AND ARE INVOLVED IN ALTERATION OF THE PHENOTYPE AND FUNCTION OF VASCULAR CELLS IN RESPONSE TO ENVIRONMENTAL STRESSES. THIS REVIEW SEEKS TO HIGHLIGHT THE RECENT ADVANCES IN OUR KNOWLEDGE OF THE EPIGENETIC REGULATIONS AND MECHANISMS OF HYPERTENSION, FOCUSING ON THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATION IN THE VASCULAR WALL. A BETTER UNDERSTANDING OF THE EPIGENOMIC REGULATION IN THE HYPERTENSIVE VESSEL MAY LEAD TO THE IDENTIFICATION OF NOVEL TARGET MOLECULES THAT, IN TURN, MAY LEAD TO NOVEL DRUG DISCOVERIES FOR THE TREATMENT OF HYPERTENSION. 2018 17 1983 46 EPIGENETIC ALTERATIONS IN PODOCYTES IN DIABETIC NEPHROPATHY. RECENTLY, EPIGENETIC ALTERATIONS HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF DIABETES AND ITS COMPLICATIONS. KIDNEY PODOCYTES, WHICH ARE GLOMERULAR EPITHELIAL CELLS, ARE IMPORTANT CELLS THAT FORM A SLIT MEMBRANE-A BARRIER FOR PROTEINURIA. PODOCYTES ARE TERMINALLY DIFFERENTIATED CELLS WITHOUT CELL DIVISION OR REPLENISHMENT ABILITIES. THEREFORE, PODOCYTE DAMAGE IS SUGGESTED TO BE ONE OF THE KEY FACTORS DETERMINING RENAL PROGNOSIS. RECENT STUDIES, INCLUDING OURS, SUGGEST THAT EPIGENETIC CHANGES IN PODOCYTES ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, THE ASSOCIATION BETWEEN DNA DAMAGE REPAIR AND EPIGENETIC CHANGES IN DIABETIC PODOCYTES HAS BEEN DEMONSTRATED. DETECTION OF PODOCYTE DNA DAMAGE AND EPIGENETIC CHANGES USING HUMAN SAMPLES, SUCH AS KIDNEY BIOPSY AND URINE-DERIVED CELLS, MAY BE A PROMISING STRATEGY FOR ESTIMATING KIDNEY DAMAGE AND RENAL PROGNOSES IN PATIENTS WITH DIABETES. TARGETING EPIGENETIC PODOCYTE CHANGES AND ASSOCIATED DNA DAMAGE MAY BECOME A NOVEL THERAPEUTIC STRATEGY FOR PREVENTING PROGRESSION TO END-STAGE RENAL DISEASE (ESRD) AND PROVIDE A POSSIBLE PROGNOSTIC MARKER IN DIABETIC NEPHROPATHY. THIS REVIEW SUMMARIZES RECENT ADVANCES REGARDING EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION, IN PODOCYTES IN DIABETIC NEPHROPATHY AND ADDRESSES DETECTION OF THESE ALTERATIONS IN HUMAN SAMPLES. ADDITIONALLY, WE FOCUSED ON DNA DAMAGE, WHICH IS INCREASED UNDER HIGH-GLUCOSE CONDITIONS AND ASSOCIATED WITH THE GENERATION OF EPIGENETIC CHANGES IN PODOCYTES. FURTHERMORE, EPIGENETIC MEMORY IN DIABETES IS DISCUSSED. UNDERSTANDING THE ROLE OF EPIGENETIC CHANGES IN PODOCYTES IN DIABETIC NEPHROPATHY MAY BE OF GREAT IMPORTANCE CONSIDERING THE INCREASING DIABETIC NEPHROPATHY PATIENT POPULATION IN AN AGING SOCIETY. 2021 18 2360 30 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 19 4668 33 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 20 5376 47 RECENT DEVELOPMENTS IN EPIGENETICS OF ACUTE AND CHRONIC KIDNEY DISEASES. THE GROWING EPIDEMIC OF OBESITY AND DIABETES, THE AGING POPULATION AS WELL AS PREVALENCE OF DRUG ABUSE HAS LED TO SIGNIFICANT INCREASES IN THE RATES OF THE CLOSELY ASSOCIATED ACUTE AND CHRONIC KIDNEY DISEASES, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, EVIDENCE SHOWS THAT PARENTAL BEHAVIOR AND DIET CAN AFFECT THE PHENOTYPE OF SUBSEQUENT GENERATIONS VIA EPIGENETIC TRANSMISSION MECHANISMS. THESE DATA SUGGEST A STRONG INFLUENCE OF THE ENVIRONMENT ON DISEASE SUSCEPTIBILITY AND THAT, APART FROM GENETIC SUSCEPTIBILITY, EPIGENETIC MECHANISMS NEED TO BE EVALUATED TO GAIN CRITICAL NEW INFORMATION ABOUT KIDNEY DISEASES. EPIGENETICS IS THE STUDY OF PROCESSES THAT CONTROL GENE EXPRESSION AND PHENOTYPE WITHOUT ALTERATIONS IN THE UNDERLYING DNA SEQUENCE. EPIGENETIC MODIFICATIONS, INCLUDING CYTOSINE DNA METHYLATION AND COVALENT POST-TRANSLATIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, ARE PART OF THE EPIGENOME, THE INTERFACE BETWEEN THE STABLE GENOME AND THE VARIABLE ENVIRONMENT. THIS DYNAMIC EPIGENETIC LAYER RESPONDS TO EXTERNAL ENVIRONMENTAL CUES TO INFLUENCE THE EXPRESSION OF GENES ASSOCIATED WITH DISEASE STATES. THE FIELD OF EPIGENETICS HAS SEEN REMARKABLE GROWTH IN THE PAST FEW YEARS WITH SIGNIFICANT ADVANCES IN BASIC BIOLOGY, CONTRIBUTIONS TO HUMAN DISEASE, AS WELL AS EPIGENOMICS TECHNOLOGIES. FURTHER UNDERSTANDING OF HOW THE RENAL CELL EPIGENOME IS ALTERED BY METABOLIC AND OTHER STIMULI CAN YIELD NOVEL NEW INSIGHTS INTO THE PATHOGENESIS OF KIDNEY DISEASES. IN THIS REVIEW, WE HAVE DISCUSSED THE CURRENT KNOWLEDGE ON THE ROLE OF EPIGENETIC MECHANISMS (PRIMARILY DNAME AND HISTONE MODIFICATIONS) IN ACUTE AND CHRONIC KIDNEY DISEASES, AND THEIR TRANSLATIONAL POTENTIAL TO IDENTIFY MUCH NEEDED NEW THERAPIES. 2015