1 2382 79 EPIGENETIC REGULATIONS IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY (DN) IS A CHRONIC COMPLICATION OF DIABETES AND THE MOST COMMON CAUSE OF END-STAGE KIDNEY DISEASE. IT HAS BEEN REPORTED THAT MULTIPLE FACTORS ARE INVOLVED IN THE PATHOGENESIS OF DN, WHILE THE MOLECULAR MECHANISMS THAT LEAD TO DN ARE STILL NOT FULLY UNDERSTOOD. NUMEROUS RISK FACTORS FOR THE DEVELOPMENT OF DIABETIC NEPHROPATHY HAVE BEEN PROPOSED, INCLUDING ETHNICITY AND INHERITED GENETIC DIFFERENCES. RECENTLY, WITH THE DEVELOPMENT OF HIGH-THROUGHPUT TECHNOLOGIES, THERE IS EMERGING EVIDENCE THAT SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF DN. EPIGENETIC REGULATIONS, INCLUDING DNA METHYLATION, NONCODING RNAS, AND HISTONE MODIFICATIONS, PLAY A PIVOTAL ROLE IN DN PATHOGENESIS BY A SECOND LAYER OF GENE REGULATION. ALL THESE FINDINGS CAN CONTRIBUTE TO DEVELOPING NOVEL THERAPIES FOR DN. 2017 2 6162 31 THE GENETICS OF DIABETIC NEPHROPATHY. UP TO 40% OF PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES WILL DEVELOP DIABETIC NEPHROPATHY (DN), RESULTING IN CHRONIC KIDNEY DISEASE AND POTENTIAL ORGAN FAILURE. THERE IS EVIDENCE FOR A HERITABLE GENETIC SUSCEPTIBILITY TO DN, BUT DESPITE INTENSIVE RESEARCH EFFORTS THE CAUSATIVE GENES REMAIN ELUSIVE. RECENTLY, GENOME-WIDE ASSOCIATION STUDIES HAVE DISCOVERED SEVERAL NOVEL GENETIC VARIANTS ASSOCIATED WITH DN. THE IDENTIFICATION OF SUCH VARIANTS MAY POTENTIALLY ALLOW FOR EARLY IDENTIFICATION OF AT RISK PATIENTS. HERE WE REVIEW THE CURRENT UNDERSTANDING OF THE KEY MOLECULAR MECHANISMS AND GENETIC ARCHITECTURE OF DN, AND DISCUSS THE MERITS OF EMPLOYING AN INTEGRATIVE APPROACH TO INCORPORATE DATASETS FROM MULTIPLE SOURCES (GENETICS, TRANSCRIPTOMICS, EPIGENETIC, PROTEOMIC) IN ORDER TO FULLY ELUCIDATE THE GENETIC ELEMENTS CONTRIBUTING TO THIS SERIOUS COMPLICATION OF DIABETES. 2013 3 6377 35 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 4 4668 37 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 5 3156 32 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 6 2613 41 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 7 2195 36 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 8 607 31 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 9 3826 38 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 10 2609 32 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 11 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 12 125 31 A SYSTEMS BIOLOGY OVERVIEW ON HUMAN DIABETIC NEPHROPATHY: FROM GENETIC SUSCEPTIBILITY TO POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL MODIFICATIONS. DIABETIC NEPHROPATHY (DN), A MICROVASCULAR COMPLICATION OCCURRING IN APPROXIMATELY 20-40% OF PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2DM), IS CHARACTERIZED BY THE PROGRESSIVE IMPAIRMENT OF GLOMERULAR FILTRATION AND THE DEVELOPMENT OF KIMMELSTIEL-WILSON LESIONS LEADING TO END-STAGE RENAL FAILURE (ESRD). THE CAUSES AND MOLECULAR MECHANISMS MEDIATING THE ONSET OF T2DM CHRONIC COMPLICATIONS ARE YET SKETCHY AND IT IS NOT CLEAR WHY DISEASE PROGRESSION OCCURS ONLY IN SOME PATIENTS. WE PERFORMED A SYSTEMATIC ANALYSIS OF THE MOST RELEVANT STUDIES INVESTIGATING GENETIC SUSCEPTIBILITY AND SPECIFIC TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND METABOLOMIC PATTERNS IN ORDER TO SUMMARIZE THE MOST SIGNIFICANT TRAITS ASSOCIATED WITH THE DISEASE ONSET AND PROGRESSION. THE PICTURE THAT EMERGES IS COMPLEX AND FASCINATING AS IT INCLUDES THE REGULATION/DYSREGULATION OF NUMEROUS BIOLOGICAL PROCESSES, CONVERGING TOWARD THE ACTIVATION OF INFLAMMATORY PROCESSES, OXIDATIVE STRESS, REMODELING OF CELLULAR FUNCTION AND MORPHOLOGY, AND DISTURBANCE OF METABOLIC PATHWAYS. THE GROWING INTEREST IN THE CHARACTERIZATION OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND THE IMPORTANCE OF HANDLING LARGE DATASETS USING A SYSTEMS BIOLOGY APPROACH ARE ALSO DISCUSSED. 2016 13 2163 34 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 14 2542 33 EPIGENETICS IN KIDNEY DISEASES. EPIGENETICS EXAMINES HERITABLE CHANGES IN DNA AND ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATION VIA EPIGENETIC REGULATORS AND NON-CODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS ARE MULTISTEP PROCESSES ASSOCIATED WITH NUMEROUS MOLECULAR ALTERATIONS EVEN IN INDIVIDUAL KIDNEY CELLS. EPIGENETIC ALTERATIONS, INCLUDING ANOMALOUS DNA METHYLATION, ABERRANT HISTONE ALTERATIONS AND CHANGES OF MICRORNA EXPRESSION ALL CONTRIBUTE TO KIDNEY PATHOGENESIS. THESE CHANGES ALTER THE GENOME-WIDE EPIGENETIC SIGNATURES AND DISRUPT ESSENTIAL PATHWAYS THAT PROTECT RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND DEVELOPMENT OF OTHER RENAL ASSOCIATED SYNDROMES. MOLECULAR CHANGES IMPACT CELLULAR FUNCTION WITHIN KIDNEY CELLS AND ITS MICROENVIRONMENT TO DRIVE AND MAINTAIN DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE EPIGENETIC MECHANISMS IN FOUR KIDNEY DISEASES INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS. WE PRIMARILY FOCUS ON CURRENT KNOWLEDGE ABOUT THE GENOME-WIDE PROFILING OF DNA METHYLATION AND HISTONE MODIFICATION, AND EPIGENETIC REGULATION ON SPECIFIC GENE(S) IN THE PATHOPHYSIOLOGY OF THESE DISEASES AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENT FOR PREVENTION AND THERAPY. INCORPORATING EPIGENOMIC TESTING INTO CLINICAL RESEARCH IS ESSENTIAL TO ELUCIDATE NOVEL EPIGENETIC BIOMARKERS AND DEVELOP PRECISION MEDICINE USING EMERGING THERAPIES. 2021 15 5660 32 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 16 859 26 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 17 4336 29 MICRORNAS: THE UNDERLYING MEDIATORS OF PATHOGENETIC PROCESSES IN VASCULAR COMPLICATIONS OF DIABETES. DIABETES MELLITUS CAUSES CHRONIC COMPLICATIONS PRIMARILY AFFECTING THE VASCULATURE OF VARIOUS ORGANS, RISKING PATIENTS FOR RENAL FAILURE, VISION LOSS AND HEART FAILURE. A NEWLY DISCOVERED CLASS OF MOLECULES, MICRORNAS, MAY BE IMPORTANT IN THE GENESIS OF THESE PATHOLOGIC PROCESSES. MICRORNAS REGULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL BY INHIBITING TARGET MESSENGER RNA TRANSLATION. IN DISEASE STATES, HOWEVER, THE EXPRESSION OF MICRORNAS OFTEN IS ALTERED, RESULTING IN FURTHER ALTERED EXPRESSION (MOSTLY OVEREXPRESSION) OF DOWNSTREAM TARGET GENES. INTERESTINGLY, RESTORING MICRORNA EXPRESSION TO NORMAL LEVELS CAN CORRECT DOWNSTREAM EFFECTS AND PREVENT DIABETES-ASSOCIATED CHANGES. INVESTIGATIONS INTO MICRORNA INVOLVED IN VARIOUS PATHOGENETIC PROCESSES MEDIATING DIABETIC NEPHROPATHY, RETINOPATHY AND CARDIOMYOPATHY ARE HIGHLIGHTED IN THIS REVIEW. FUTURE DIRECTIONS OF MICRORNA IN THERAPEUTICS AND DIAGNOSTICS ARE ALSO DISCUSSED. IT IS OUR INTENT TO HELP THE READER APPRECIATE THE DIVERSE INTERACTIONS MICRORNAS HAVE IN CELLULAR SIGNALLING AND HOW UNDERSTANDING EPIGENETIC ELEMENTS, SUCH AS MICRORNAS, POTENTIALLY CAN YIELD NEW THERAPEUTIC STRATEGIES. 2013 18 4250 33 METHYLATION-DEMETHYLATION DYNAMICS: IMPLICATIONS OF CHANGES IN ACUTE KIDNEY INJURY. OVER THE YEARS, THE EPIGENETIC LANDSCAPE HAS GROWN INCREASINGLY COMPLEX. UNTIL RECENTLY, METHYLATION OF DNA AND HISTONES WAS CONSIDERED ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS. HOWEVER, WITH THE DISCOVERY OF ENZYMES INVOLVED IN THE DEMETHYLATION PROCESS, SEVERAL EXCITING PROSPECTS HAVE EMERGED THAT FOCUS ON THE DYNAMIC REGULATION OF METHYLATION AND ITS CRUCIAL ROLE IN DEVELOPMENT AND DISEASE. AN INTERPLAY OF THE METHYLATION-DEMETHYLATION MACHINERY CONTROLS THE PROCESS OF GENE EXPRESSION. SINCE ACUTE KIDNEY INJURY (AKI), A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE AND DEATH, IS CHARACTERISED BY ABERRANT EXPRESSION OF GENES, UNDERSTANDING THE DYNAMICS OF METHYLATION AND DEMETHYLATION WILL PROVIDE NEW INSIGHTS INTO THE INTRICACIES OF THE DISEASE. RESEARCH ON EPIGENETICS IN AKI HAS ONLY MADE ITS MARK IN THE RECENT YEARS BUT HAS PROVIDED COMPELLING EVIDENCE THAT IMPLICATES THE INVOLVEMENT OF METHYLATION AND DEMETHYLATION CHANGES IN ITS PATHOPHYSIOLOGY. IN THIS REVIEW, WE EXPLORE THE ROLE OF METHYLATION AND DEMETHYLATION MACHINERY IN CELLULAR EPIGENETIC CONTROL AND FURTHER DISCUSS THE CONTRIBUTION OF METHYLOMIC CHANGES AND HISTONE MODIFICATIONS TO THE PATHOPHYSIOLOGY OF AKI. 2018 19 2579 23 EPIGENETICS OF KIDNEY DISEASE. DNA METHYLATION AND HISTONE MODIFICATIONS DETERMINE RENAL PROGRAMMING AND THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. THE IDENTIFICATION OF THE WAY IN WHICH THE RENAL CELL EPIGENOME IS ALTERED BY ENVIRONMENTAL MODIFIERS DRIVING THE ONSET AND PROGRESSION OF RENAL DISEASES HAS EXTENDED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF KIDNEY DISEASE PROGRESSION. IN THIS REVIEW, WE FOCUS ON CURRENT KNOWLEDGE CONCERNING THE IMPLICATIONS OF EPIGENETIC MODIFICATIONS DURING RENAL DISEASE FROM EARLY DEVELOPMENT TO CHRONIC KIDNEY DISEASE PROGRESSION INCLUDING RENAL FIBROSIS, DIABETIC NEPHROPATHY AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENTS FOR THE PREVENTION AND THERAPY OF CHRONIC KIDNEY DISEASE AND END-STAGE KIDNEY DISEASE. 2017 20 5376 40 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