1 2613 135 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 2 3156 49 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 3 2163 59 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 4 2190 73 EPIGENETIC MECHANISMS. THE INCIDENCE OF DIABETES AND RELATED COMPLICATIONS LIKE NEPHROPATHY IS GROWING RAPIDLY AND HAS BECOME A MAJOR HEALTH CARE ISSUE. CHANGES IN THE ENVIRONMENT AND NUTRITIONAL HABITS HAVE BEEN IMPLICATED AS MAJOR PLAYERS. FURTHERMORE, IT IS BECOMING INCREASINGLY CLEAR THAT EPIGENETIC FACTORS MAY MODULATE THE CONNECTIONS BETWEEN GENES AND THE ENVIRONMENT. WHILE DIABETES IN ITSELF IS TREATABLE TO A LARGE EXTENT, IT IS STILL ASSOCIATED WITH SIGNIFICANTLY INCREASED RISK FOR COMPLICATIONS INCLUDING CHRONIC KIDNEY AND CARDIOVASCULAR DISEASES. CURRENT TREATMENTS HAVE ADDED PREVENTATIVE APPROACHES SO AS TO AVOID FUTURE DIABETIC COMPLICATIONS. UNFORTUNATELY, DIABETIC PATIENTS ARE OFTEN PLAGUED WITH THE CONTINUED DEVELOPMENT OF VARIOUS COMPLICATIONS EVEN AFTER ACHIEVING GLUCOSE CONTROL. THIS HAS BEEN SUGGESTED TO BE ATTRIBUTABLE TO A MYSTERIOUS PHENOMENON TERMED 'METABOLIC MEMORY' OF THE PRIOR GLYCEMIC STATE. RECENT STUDIES HAVE SUGGESTED THAT EPIGENETIC CHANGES TO CHROMATIN CAN AFFECT GENE EXPRESSION IN RESPONSE TO VARIOUS STIMULI, AND CHANGES IN KEY BIOCHEMICAL PATHWAYS AND EPIGENETIC HISTONE AND DNA METHYLATION PATTERNS IN CHROMATIN HAVE BEEN OBSERVED IN A DIABETIC MILIEU. THESE ACCUMULATING DATA SUGGEST THAT METABOLIC OR HYPERGLYCEMIC MEMORY MAY BE DUE TO EPIGENETIC CHANGES IN SPECIFIC TARGET TISSUES ALTERING GENE EXPRESSION WITHOUT CHANGING THE GENETIC CODE ITSELF. WHILE THE GENETICS OF DIABETES HAS LONG BEEN THE FOCUS OF SCIENTIFIC RESEARCH, MUCH LESS IS KNOWN ABOUT THE ROLE OF EPIGENETICS AND THE RELATED MOLECULAR PATHWAYS THAT MIGHT AFFECT THE DEVELOPMENT OF DIABETES AND THE ASSOCIATED COMPLICATIONS. FURTHER STUDIES OF EPIGENETIC MECHANISMS ARE THEREFORE TIMELY AND COULD PROVIDE VALUABLE NEW INSIGHTS INTO THE PATHOLOGY OF DIABETIC COMPLICATIONS AND ALSO UNCOVER MUCH NEEDED NEW THERAPEUTIC TARGETS. 2011 5 6341 44 THE ROLE OF EPIGENETIC MODIFICATIONS IN LATE COMPLICATIONS IN TYPE 1 DIABETES. TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE IN WHICH THE DESTRUCTION OF PANCREATIC BETA CELLS LEADS TO HYPERGLYCEMIA. THE PREVENTION OF HYPERGLYCEMIA IS VERY IMPORTANT TO AVOID OR AT LEAST POSTPONE THE DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS, ALSO KNOWN AS LATE COMPLICATIONS. THESE INCLUDE DIABETIC RETINOPATHY, CHRONIC RENAL FAILURE, DIABETIC NEUROPATHY, AND CARDIOVASCULAR DISEASES. THE IMPACT OF LONG-TERM HYPERGLYCEMIA HAS BEEN SHOWN TO PERSIST LONG AFTER THE NORMALIZATION OF BLOOD GLUCOSE LEVELS, A PHENOMENON KNOWN AS METABOLIC MEMORY. IT IS BELIEVED THAT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, PLAY AN IMPORTANT ROLE IN METABOLIC MEMORY. THE AIM OF THIS REVIEW IS TO ADDRESS THE IMPACT OF LONG-TERM HYPERGLYCEMIA ON EPIGENETIC MARKS IN LATE COMPLICATIONS OF TYPE 1 DIABETES. 2022 6 607 46 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 7 2491 43 EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. TYPE 2 DIABETES HAS BECOME A MAJOR HEALTH ISSUE WORLDWIDE. CHRONIC HYPERGLYCEMIA INDUCES A LOW-GRADE INFLAMMATION THAT, ON TOP OF OTHER MECHANISMS, LEADS TO ENDOTHELIAL DYSFUNCTION. MOUNTING EVIDENCE SUGGESTS THAT DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, AND LONG NON-CODING RNAS PLAY AN IMPORTANT ROLE IN THE INITIATION, MAINTENANCE, AND PROGRESSION OF BOTH MACRO- AND MICRO-VASCULAR COMPLICATIONS OF DIABETES. LONG-TERM EXPOSURE TO HYPERGLYCEMIA INDUCES EPIGENETIC CHANGES THAT COULD BECOME IRREVERSIBLE, A PHENOMENON KNOWN AS THE 'METABOLIC MEMORY.' WHETHER EPIGENETIC-BASED THERAPIES COULD BE USED TO SLOW OR LIMIT THE PROGRESSION OF CARDIOVASCULAR DISEASE REMAINS UNCLEAR. WHILE NON-CODING RNAS ARE CURRENTLY INVESTIGATED AS POTENTIAL BIOMARKERS THAT PREDICT DIABETIC CARDIOVASCULAR DISEASE INCIDENCE AND PROGRESSION, THEIR THERAPEUTIC ROLE IS ONLY HYPOTHETICAL. IN THIS REVIEW, WE HIGHLIGHT THE LATEST FINDINGS IN EXPERIMENTAL AND CLINICAL STUDIES RELEVANT TO EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. 2015 8 3748 48 INSIGHTS INTO THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING IN DIABETES MELLITUS. BACKGROUND: DIABETES MELLITUS IS A METABOLIC DISORDER THAT IS CHARACTERIZED BY IMPAIRED GLUCOSE TOLERANCE RESULTING FROM DEFECTS IN INSULIN SECRETION, INSULIN ACTION, OR BOTH. EPIGENETIC MODIFICATIONS, WHICH ARE DEFINED AS INHERITED CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN GENE SEQUENCE, ARE INVOLVED IN THE ETIOLOGY OF DIABETES. METHODS: IN THIS REVIEW, WE FOCUSED ON THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING AND THEIR CONTRIBUTION TO THE DEVELOPMENT OF BOTH TYPE 1 AND TYPE 2 DIABETES MELLITUS. RESULTS: CHANGES IN DNA METHYLATION IN PARTICULAR ARE HIGHLY ASSOCIATED WITH THE DEVELOPMENT OF DIABETES. PROTEIN FUNCTION IS DEPENDENT ON THEIR PROPER FOLDING IN THE ENDOPLASMIC RETICULUM. DEFECTIVE PROTEIN FOLDING AND CONSEQUENTLY THEIR FUNCTIONS HAVE ALSO BEEN REPORTED TO PLAY A ROLE. EARLY TREATMENT OF DIABETES HAS PROVEN TO BE OF GREAT BENEFIT, AS EVEN TRANSIENT HYPERGLYCEMIA MAY LEAD TO PATHOLOGICAL EFFECTS AND COMPLICATIONS LATER ON. THIS HAS BEEN EXPLAINED BY THE THEORY OF THE DEVELOPMENT OF A METABOLIC MEMORY IN DIABETES. THE BASIS FOR THIS METABOLIC MEMORY WAS ATTRIBUTED TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, NON-ENZYMATIC GLYCATION OF PROTEINS AND IMPORTANTLY, EPIGENETIC CHANGES. THIS HIGHLIGHTS THE IMPORTANCE OF LINKING NEW THERAPEUTICS TARGETING EPIGENETIC MECHANISMS WITH TRADITIONAL ANTIDIABETIC DRUGS. CONCLUSION: ALTHOUGH NEW DATA IS EVOLVING ON THE RELATION BETWEEN DNA METHYLATION, PROTEIN MISFOLDING, AND THE ETIOLOGY OF DIABETES, MORE STUDIES ARE REQUIRED FOR DEVELOPING NEW RELEVANT DIAGNOSTICS AND THERAPEUTICS. 2019 9 2154 55 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 5376 52 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 11 4192 41 METABOLIC MEMORY AND CHRONIC DIABETES COMPLICATIONS: POTENTIAL ROLE FOR EPIGENETIC MECHANISMS. RECENT ESTIMATES INDICATE THAT DIABETES MELLITUS CURRENTLY AFFECTS MORE THAN 10 % OF THE WORLD'S POPULATION. EVIDENCE FROM BOTH THE LABORATORY AND LARGE SCALE CLINICAL TRIALS HAS REVEALED THAT PROLONGED HYPERGLYCEMIA INDUCES CHRONIC COMPLICATIONS WHICH PERSIST AND PROGRESS UNIMPEDED EVEN WHEN GLYCEMIC CONTROL IS PHARMACEUTICALLY ACHIEVED VIA THE PHENOMENON OF METABOLIC MEMORY. THE EPIGENOME IS COMPRISED OF ALL CHROMATIN MODIFICATIONS INCLUDING POST TRANSLATIONAL HISTONE MODIFICATION, EXPRESSION CONTROL VIA MIRNAS AND THE METHYLATION OF CYTOSINE WITHIN DNA. MODIFICATIONS OF THESE EPIGENETIC MARKS NOT ONLY ALLOW CELLS AND ORGANISMS TO QUICKLY RESPOND TO CHANGING ENVIRONMENTAL STIMULI BUT ALSO CONFER THE ABILITY OF THE CELL TO "MEMORIZE" THESE ENCOUNTERS. AS SUCH, THESE PROCESSES HAVE GAINED MUCH ATTENTION AS POTENTIAL MOLECULAR MECHANISMS UNDERLYING METABOLIC MEMORY AND CHRONIC DIABETIC COMPLICATIONS. HERE WE PRESENT A REVIEW OF THE VERY RECENT LITERATURE PUBLISHED PERTAINING TO THIS SUBJECT. 2012 12 2028 43 EPIGENETIC CHANGES IN DIABETES. DIABETES IS A MULTIFACTORIAL DISEASE WITH NUMEROUS PATHWAYS INFLUENCING ITS PROGRESSION AND RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR BY GENETIC PREDISPOSITION. A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. EPIGENETIC PROCESSES AT THE CHROMATIN TEMPLATE SIGNIFICANTLY SENSITIZE TRANSCRIPTIONAL AND PHENOTYPIC OUTCOMES TO ENVIRONMENTAL SIGNALING INFORMATION INCLUDING METABOLIC STATE, NUTRITIONAL REQUIREMENTS AND HISTORY. EPIGENETIC MECHANISMS IMPACT GENE EXPRESSION THAT COULD PREDISPOSE INDIVIDUALS TO THE DIABETIC PHENOTYPE DURING INTRAUTERINE AND EARLY POSTNATAL DEVELOPMENT, AS WELL AS THROUGHOUT ADULT LIFE. FURTHERMORE, EPIGENETIC CHANGES COULD ACCOUNT FOR THE ACCELERATED RATES OF CHRONIC AND PERSISTENT MICROVASCULAR AND MACROVASCULAR COMPLICATIONS ASSOCIATED WITH DIABETES. EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES IDENTIFIED POOR GLYCEMIC CONTROL AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF DIABETIC COMPLICATIONS AND HIGHLIGHT THE REQUIREMENT FOR EARLY INTERVENTION. EARLY EXPOSURE TO HYPERGLYCEMIA CAN DRIVE THE DEVELOPMENT OF COMPLICATIONS THAT MANIFEST LATE IN THE PROGRESSION OF THE DISEASE AND PERSIST DESPITE IMPROVED GLYCEMIC CONTROL, INDICATING A MEMORY OF THE METABOLIC INSULT. UNDERSTANDING THE MOLECULAR EVENTS THAT UNDERLIE THESE TRANSCRIPTIONAL CHANGES WILL SIGNIFICANTLY CONTRIBUTE TO NOVEL THERAPEUTIC INTERVENTIONS TO PREVENT, REVERSE OR RETARD THE DELETERIOUS EFFECTS OF THE DIABETIC MILIEU. 2013 13 6129 45 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 14 4193 50 METABOLIC MEMORY AND DIABETIC NEPHROPATHY: BENEFICIAL EFFECTS OF NATURAL EPIGENETIC MODIFIERS. NEPHROPATHY IS ONE OF THE MOST FREQUENT COMPLICATIONS OF CHRONIC DIABETES. THE MAIN REASON FOR NEPHROPATHY DESPITE BEING HYPERGLYCEMIA, BUT IT PROGRESSES EVEN AFTER GOOD GLYCEMIC CONTROL HAS BEEN ACHIEVED IN DIABETIC PATIENTS. THE EFFECTS OF PRIOR EXPOSURE TO HIGH BLOOD GLUCOSE CONDITIONS DEPEND UPON THE SEVERITY AND DURATION OF THIS EXPOSURE, INDICATING A "METABOLIC MEMORY" PHENOMENON. HYPERGLYCEMIA NOT ONLY INCREASES OXIDATIVE STRESS BUT IS ALSO ALLEGED TO START SEVERAL BIOCHEMICAL ANOMALIES AND ALTER GENE EXPRESSION ASSOCIATED WITH METABOLIC HOMEOSTASIS. HIGH GLUCOSE LEVELS INDUCE EPIGENETIC MODIFICATIONS THAT ALTER GENE EXPRESSION WITHOUT CHANGING DNA SEQUENCES. THESE EPIGENETIC MODIFICATIONS HAVE SHOWN TO BE REVERSIBLE AND HAVE THE POTENTIAL TO CEASE ADVERSE EFFECTS IF GOOD GLYCEMIC CONTROL IS ACHIEVED FROM INITIATION OF DIABETES. HOWEVER, IF GOOD GLYCEMIC CONTROL IS NOT ACHIEVED FOR MONTHS, THESE MODIFICATIONS STAND FIRM TO REVERSALS. THERAPIES AND DRUGS HAVE BEEN IN USE TO PREVENT EPIGENETIC MODIFICATIONS AND OXIDATIVE STRESS, WHICH ALSO HELPED IN AMELIORATING DIABETIC NEPHROPATHY. BUT THESE SYNTHETIC DRUGS ARE LOADED WITH SIDE EFFECTS LIKE INCREASED BODY WEIGHT, KIDNEY DYSFUNCTION ETC. SO PHYTOCHEMICALS ARE EMERGING AS ALTERNATIVES AND MANY OF THEM HAVE ALREADY BEEN USED TO TREAT NEPHROPATHY. BUT STILL, THERE IS RIGOROUS NEED TO EVALUATE PHYTOCHEMICALS WHICH CAN REGULATE EPIGENETIC EVENTS AND HAVE THE POTENTIAL TO DECELERATE THE FURTHER PROGRESSION OF THESE LIFE-THREATENING DISEASES. IN THIS REVIEW ARTICLE WE DISCUSS THE POTENTIAL EPIGENETIC MODIFIERS FROM PLANTS THAT CAN ERASE METABOLIC MEMORY AND CAN THUS BE PROTECTIVE AGAINST DIABETIC NEPHROPATHY. 2020 15 2965 59 GENETIC AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC RETINOPATHY: A MOLECULAR LINK TO REGULATE GENE EXPRESSION. INTENSIFICATION IN THE FREQUENCY OF DIABETES AND THE ASSOCIATED VASCULAR COMPLICATIONS HAS BEEN A ROOT CAUSE OF BLINDNESS AND VISUAL IMPAIRMENT WORLDWIDE. ONE SUCH VASCULAR COMPLICATION WHICH HAS BEEN THE PROMINENT CAUSE OF BLINDNESS; RETINAL VASCULATURE, NEURONAL AND GLIAL ABNORMALITIES IS DIABETIC RETINOPATHY (DR), A CHRONIC COMPLICATED OUTCOME OF TYPE 1 AND TYPE 2 DIABETES. IT HAS ALSO BECOME CLEAR THAT "GENETIC" VARIATIONS IN POPULATION ALONE CAN'T EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETES AND ITS COMPLICATIONS INCLUDING DR. DR EXPERIENCES ENGAGEMENT OF FOREMOST MEDIATORS OF DIABETES SUCH AS HYPERGLYCEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS THAT LEAD TO THE DYSREGULATION OF "EPIGENETIC" MECHANISMS INVOLVING HISTONE ACETYLATION AND HISTONE AND DNA METHYLATION, CHROMATIN REMODELING AND EXPRESSION OF A COMPLEX SET OF STRESS-REGULATED AND DISEASE-ASSOCIATED GENES. IN ADDITION, BOTH ELEVATED GLUCOSE CONCENTRATION AND INSULIN RESISTANCE LEAVE A ROBUST EFFECT ON EPIGENETIC REPROGRAMMING OF THE ENDOTHELIAL CELLS TOO, SINCE ENDOTHELIUM ASSOCIATED WITH THE EYE AIDS IN MAINTAINING THE VASCULAR HOMEOSTASIS. FURTHERMORE, SEVERAL STUDIES CONDUCTED ON THE DISEASE SUGGEST THAT THE MODIFICATIONS OF THE EPIGENOME MIGHT BE THE FUNDAMENTAL MECHANISM(S) FOR THE PROPOSED METABOLIC MEMORY' RESULTING INTO PROLONGED GENE EXPRESSION FOR INFLAMMATION AND CELLULAR DYSFUNCTION EVEN AFTER ATTAINING THE GLYCEMIC CONTROL IN DIABETICS. HENCEFORTH, THE PRESENT REVIEW FOCUSES ON THE ASPECTS OF GENETIC AND EPIGENETIC ALTERATIONS IN GENES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR AND ALDOSE REDUCTASE CONSIDERED BEING ASSOCIATED WITH DR. IN ADDITION, WE DISCUSS BRIEFLY THE ROLE OF THE THIOREDOXIN-INTERACTING PROTEIN TXNIP, WHICH IS STRONGLY INDUCED BY HIGH GLUCOSE AND DIABETES, IN CELLULAR OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION POTENTIALLY LEADING TO CHROMATIN REMODELING AND OCULAR COMPLICATIONS OF DIABETES. THE IDENTIFICATION OF DISEASE-ASSOCIATED GENES AND THEIR EPIGENETIC REGULATIONS WILL LEAD TO POTENTIAL NEW DRUGS AND GENE THERAPIES AS WELL AS PERSONALIZED MEDICINE TO PREVENT OR SLOW DOWN THE PROGRESSION OF DR. 2016 16 2195 46 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 17 6377 44 THE ROLE OF NON-CODING RNAS IN DIABETIC NEPHROPATHY: POTENTIAL APPLICATIONS AS BIOMARKERS FOR DISEASE DEVELOPMENT AND PROGRESSION. DIABETIC NEPHROPATHY, A PROGRESSIVE KIDNEY DISEASE THAT DEVELOPS SECONDARY TO DIABETES, IS THE MAJOR CAUSE OF CHRONIC KIDNEY DISEASE IN DEVELOPED COUNTRIES, AND CONTRIBUTES SIGNIFICANTLY TO INCREASED MORBIDITY AND MORTALITY AMONG INDIVIDUALS WITH DIABETES. ALTHOUGH THE CAUSES OF DIABETIC NEPHROPATHY ARE NOT FULLY UNDERSTOOD, RECENT STUDIES DEMONSTRATE A ROLE FOR EPIGENETIC FACTORS IN THE DEVELOPMENT OF THE DISEASE. FOR EXAMPLE, NON-CODING RNA (NCRNA) MOLECULES, INCLUDING MICRORNAS (MIRNAS), HAVE BEEN SHOWN TO BE FUNCTIONALLY IMPORTANT IN MODULATING RENAL RESPONSE TO HYPERGLYCEMIA AND PROGRESSION OF DIABETIC NEPHROPATHY. CHARACTERIZATION OF MIRNA EXPRESSION IN DIABETIC NEPHROPATHY FROM STUDIES OF ANIMAL MODELS OF DIABETES, AND IN VITRO INVESTIGATIONS USING DIFFERENT TYPES OF KIDNEY CELLS ALSO SUPPORT THIS ROLE. THE GOAL OF THIS REVIEW, THEREFORE, IS TO SUMMARIZE THE CURRENT STATE OF KNOWLEDGE OF SPECIFIC NCRNAS INVOLVED IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, WITH A FOCUS ON THE POTENTIAL ROLE OF MIRNAS TO SERVE AS SENSITIVE, NON-INVASIVE BIOMARKERS OF KIDNEY DISEASE AND PROGRESSION. NON-CODING RNAS ARE CURRENTLY RECOGNIZED AS POTENTIALLY IMPORTANT REGULATORS OF GENES INVOLVED IN PROCESSES RELATED TO THE DEVELOPMENT OF DIABETIC NEPHROPATHY, AND AS SUCH, REPRESENT VIABLE TARGETS FOR BOTH CLINICAL DIAGNOSTIC STRATEGIES AND THERAPEUTIC INTERVENTION. 2013 18 2062 35 EPIGENETIC CONTROL OF HYPERTENSION BY DNA METHYLATION: A REAL POSSIBILITY. HYPERTENSION IS A COMMON CHRONIC DISEASE THAT PARTICULARLY AFFECTS THE ELDERLY AND CAN TRIGGER SEVERAL CARDIOVASCULAR CONDITIONS. ALTHOUGH THE TREATMENT OF HYPERTENSION HAS EVOLVED IN RECENT DECADES, MANY HYPERTENSIVE PATIENTS STILL DO NOT HAVE PROPERLY CONTROLLED BLOOD PRESSURE. ACCUMULATING EVIDENCE SUPPORTS THE HYPOTHESIS THAT DNA METHYLATION PLAYS AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION, ALTERING THE PHENOTYPE AND FUNCTION OF THE CARDIOVASCULAR SYSTEM. THE PRESENT REVIEW HIGHLIGHTS RECENT ADVANCES IN RESEARCH ON DNA METHYLATION IN THE DEVELOPMENT OF HYPERTENSION. SEVERAL PRECLINICAL AND CLINICAL EVIDENCE SHOW THAT METHYLATION OF DIFFERENT TARGETS APPEARS TO BE INVOLVED IN HYPERTENSION. STUDIES OF THE INVOLVEMENT OF DNA METHYLATION HAVE GREATLY IMPROVED OUR UNDERSTANDING OF HYPERTENSION, BUT ITS USE AS A VALID THERAPEUTIC TARGET IS STILL UNKNOWN. FURTHER STUDIES COULD HELP TO BRING TO LIGHT THE TRUTH ABOUT GENE THERAPY IN HYPERTENSION. 2021 19 1505 39 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 20 859 37 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