1 2579 61 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 2 2195 30 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 3 5660 31 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 4 2542 39 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 5 3826 30 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 6 2555 25 EPIGENETICS IN RENAL DISEASES. WITH AGING, PREVALENCE OF OBESITY, HYPERTENSION, DIABETES AND RENAL DISEASES HAVE INCREASED GLOBALLY. OVER THE LAST TWO DECADES, THE PREVALENCE OF RENAL DISEASES HAS BEEN INTENSELY INCREASING. RENAL DISEASE AND RENAL PROGRAMMING ARE REGULATED BY EPIGENETIC MODIFICATIONS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS. ENVIRONMENTAL FACTORS HAVE SIGNIFICANT ROLE IN THE PATHOPHYSIOLOGY OF RENAL DISEASE PROGRESSION. UNDERSTANDING THE POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION MAY BE USEFUL IN RENAL DISEASE PROGNOSIS, DIAGNOSIS AND PROVIDES NOVEL THERAPEUTIC MEASURES. IN A NUTSHELL, THIS CHAPTER TALKS ABOUT THE ROLE OF EPIGENETIC MECHANISMS-DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNA IN DIFFERENT RENAL DISEASES. THESE INCLUDE DIABETIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, RENAL FIBROSIS, ETC. 2023 7 6638 23 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 6377 27 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 9 4668 25 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 10 5364 29 RECENT ADVANCES IN EPIGENETICS OF AGE-RELATED KIDNEY DISEASES. RENAL AGING HAS ATTRACTED INCREASING ATTENTION IN TODAY'S AGING SOCIETY, AS ELDERLY PEOPLE WITH ADVANCED AGE ARE MORE SUSCEPTIBLE TO VARIOUS KIDNEY DISORDERS SUCH AS ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD). THERE IS NO CLEAR-CUT UNIVERSAL MECHANISM FOR IDENTIFYING AGE-RELATED KIDNEY DISEASES, AND THEREFORE, THEY POSE A CONSIDERABLE MEDICAL AND PUBLIC HEALTH CHALLENGE. EPIGENETICS REFERS TO THE STUDY OF HERITABLE MODIFICATIONS IN THE REGULATION OF GENE EXPRESSION THAT DO NOT REQUIRE CHANGES IN THE UNDERLYING GENOMIC DNA SEQUENCE. A VARIETY OF EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASES (HDAC) INHIBITORS AND DNA METHYLTRANSFERASE (DNMT) INHIBITORS HAVE BEEN PROPOSED AS POTENTIAL BIOMARKERS AND THERAPEUTIC TARGETS IN NUMEROUS FIELDS INCLUDING CARDIOVASCULAR DISEASES, IMMUNE SYSTEM DISEASE, NERVOUS SYSTEM DISEASES, AND NEOPLASMS. ACCUMULATING EVIDENCE IN RECENT YEARS INDICATES THAT EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN RENAL AGING. HOWEVER, NO PREVIOUS SYSTEMATIC REVIEW HAS BEEN PERFORMED TO SYSTEMATICALLY GENERALIZE THE RELATIONSHIP BETWEEN EPIGENETICS AND AGE-RELATED KIDNEY DISEASES. IN THIS REVIEW, WE AIM TO SUMMARIZE THE RECENT ADVANCES IN EPIGENETIC MECHANISMS OF AGE-RELATED KIDNEY DISEASES AS WELL AS DISCUSS THE APPLICATION OF EPIGENETIC MODIFIERS AS POTENTIAL BIOMARKERS AND THERAPEUTIC TARGETS IN THE FIELD OF AGE-RELATED KIDNEY DISEASES. IN SUMMARY, THE MAIN TYPES OF EPIGENETIC PROCESSES INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA (NCRNA) MODULATION HAVE ALL BEEN IMPLICATED IN THE PROGRESSION OF AGE-RELATED KIDNEY DISEASES, AND THERAPEUTIC TARGETING OF THESE PROCESSES WILL YIELD NOVEL THERAPEUTIC STRATEGIES FOR THE PREVENTION AND/OR TREATMENT OF AGE-RELATED KIDNEY DISEASES. 2022 11 2286 23 EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION. KIDNEY TRANSPLANTATION IS A STANDARD CARE FOR END STAGE RENAL DISEASE, BUT IT IS ALSO ASSOCIATED WITH A COMPLEX PATHOGENESIS INCLUDING ISCHEMIA-REPERFUSION INJURY, INFLAMMATION, AND DEVELOPMENT OF FIBROSIS. OVER THE PAST DECADE, ACCUMULATING EVIDENCE HAS SUGGESTED A ROLE OF EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION, INVOLVING DNA METHYLATION, HISTONE MODIFICATION, AND VARIOUS KINDS OF NON-CODING RNAS. HERE, WE ANALYZE THESE RECENT STUDIES SUPPORTING THE ROLE OF EPIGENETIC REGULATION IN DIFFERENT PATHOLOGICAL PROCESSES OF KIDNEY TRANSPLANTATION, I.E., ISCHEMIA-REPERFUSION INJURY, ACUTE REJECTION, AND CHRONIC GRAFT PATHOLOGIES INCLUDING RENAL INTERSTITIAL FIBROSIS. FURTHER INVESTIGATION OF EPIGENETIC ALTERATIONS, THEIR PATHOLOGICAL ROLES AND UNDERLYING MECHANISMS IN KIDNEY TRANSPLANTATION MAY LEAD TO NEW STRATEGIES FOR THE DISCOVERY OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2022 12 5370 19 RECENT ADVANCES IN UNDERSTANDING OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED AS ANY CONDITION THAT CAUSES REDUCED KIDNEY FUNCTION OVER A PERIOD OF TIME. FIBROSIS, TUBULAR ATROPHY AND INTERSTITIAL INFLAMMATION ARE THE HALLMARK OF PATHOLOGICAL FEATURES IN CKD. REGARDLESS OF INITIAL INSULT, CKD HAS SOME COMMON PATHWAYS LEADING CKD TO END-STAGE KIDNEY DISEASE, INCLUDING HYPOXIA IN THE TUBULOINTERSTITIUM AND PROTEINURIA. RECENT ADVANCES IN GENOME EDITING TECHNOLOGIES AND STEM CELL RESEARCH GIVE GREAT INSIGHTS TO UNDERSTAND THE PATHOGENESIS OF CKD, INCLUDING IDENTIFICATIONS OF THE ORIGINS OF RENAL MYOFIBROBLASTS AND TUBULAR EPITHELIAL CELLS UPON INJURY. ENVIRONMENTAL FACTORS SUCH AS HYPOXIA, OXIDATIVE STRESS, AND EPIGENETIC FACTORS IN RELATION TO CKD ARE ALSO DISCUSSED. 2015 13 859 22 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 14 6075 26 THE DYNAMICS AND PLASTICITY OF EPIGENETICS IN DIABETIC KIDNEY DISEASE: THERAPEUTIC APPLICATIONS VIS-A-VIS. CHRONIC KIDNEY DISEASE (CKD) REFERS TO THE PHENOMENON OF PROGRESSIVE DECLINE IN THE GLOMERULAR FILTRATION RATE ACCOMPANIED BY ADVERSE CONSEQUENCES, INCLUDING FLUID RETENTION, ELECTROLYTE IMBALANCE, AND AN INCREASED CARDIOVASCULAR RISK COMPARED TO THOSE WITH NORMAL RENAL FUNCTION. THE TRIGGERS FOR THE IRREVERSIBLE RENAL FUNCTION DETERIORATION ARE MULTIFACTORIAL, AND DIABETES MELLITUS SERVES AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF CKD, NAMELY DIABETIC KIDNEY DISEASE (DKD). RECENTLY, EPIGENETIC DYSREGULATION EMERGED AS A PIVOTAL PLAYER STEERING THE PROGRESSION OF DKD, PARTLY RESULTING FROM HYPERGLYCEMIA-ASSOCIATED METABOLIC DISTURBANCES, RISING OXIDATIVE STRESS, AND/OR UNCONTROLLED INFLAMMATION. IN THIS REVIEW, WE DESCRIBE THE MAJOR EPIGENETIC MOLECULAR MECHANISMS, FOLLOWED BY SUMMARIZING CURRENT UNDERSTANDINGS OF THE EPIGENETIC ALTERATIONS PERTAINING TO DKD. WE HIGHLIGHT THE EPIGENETIC REGULATORY PROCESSES INVOLVED IN SEVERAL CRUCIAL RENAL CELL TYPES: MESANGIAL CELLS, PODOCYTES, TUBULAR EPITHELIA, AND GLOMERULAR ENDOTHELIAL CELLS. FINALLY, WE HIGHLIGHT EPIGENETIC BIOMARKERS AND RELATED THERAPEUTIC CANDIDATES THAT HOLD PROMISING POTENTIAL FOR THE EARLY DETECTION OF DKD AND THE AMELIORATION OF ITS PROGRESSION. 2022 15 2193 27 EPIGENETIC MODIFICATION DRIVES ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) IS A COMMON CLINICAL CRITICAL DISEASE. DUE TO ITS HIGH MORBIDITY, INCREASING RISK OF COMPLICATIONS, HIGH MORTALITY RATE, AND HIGH MEDICAL COSTS, IT HAS BECOME A GLOBAL CONCERN FOR HUMAN HEALTH PROBLEMS. INITIALLY, RESEARCHERS BELIEVED THAT KIDNEYS HAVE A STRONG ABILITY TO REGENERATE AND REPAIR, BUT STUDIES OVER THE PAST 20 YEARS HAVE FOUND THAT KIDNEYS DAMAGED BY AKI ARE OFTEN INCOMPLETE OR EVEN UNABLE TO REPAIR. EVEN WHEN SERUM CREATININE RETURNS TO BASELINE LEVELS, RENAL STRUCTURAL DAMAGE PERSISTS FOR A LONG TIME, LEADING TO THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE MECHANISM OF AKI-TO-CKD TRANSITION HAS NOT BEEN FULLY ELUCIDATED. AS AN IMPORTANT REGULATOR OF GENE EXPRESSION, EPIGENETIC MODIFICATIONS, SUCH AS HISTONE MODIFICATION, DNA METHYLATION, AND NONCODING RNAS, MAY PLAY AN IMPORTANT ROLE IN THIS PROCESS. ALTERATIONS IN EPIGENETIC MODIFICATION ARE INDUCED BY HYPOXIA, THUS PROMOTING THE EXPRESSION OF INFLAMMATORY FACTOR-RELATED GENES AND COLLAGEN SECRETION. THIS REVIEW ELABORATED THE ROLE OF EPIGENETIC MODIFICATIONS IN AKI-TO-CKD PROGRESSION, THE DIAGNOSTIC VALUE OF EPIGENETIC MODIFICATIONS BIOMARKERS IN AKI CHRONIC OUTCOME, AND THE POTENTIAL ROLE OF TARGETING EPIGENETIC MODIFICATIONS IN THE PREVENTION AND TREATMENT OF AKI TO CKD, IN ORDER TO PROVIDE IDEAS FOR THE SUBSEQUENT ESTABLISHMENT OF TARGETED THERAPEUTIC STRATEGIES TO PREVENT THE PROGRESSION OF RENAL TUBULAR-INTERSTITIAL FIBROSIS. 2021 16 4456 21 MOLECULAR MECHANISMS IN RENAL DEGENERATIVE DISEASE. CHRONIC KIDNEY DISEASE (CKD) HAS BECOME A MAJOR PUBLIC HEALTH PROBLEM WORLDWIDE. THEREFORE, A CONSIDERABLE EFFORT IS CURRENTLY DIRECTED TO UNDERSTAND THE MOLECULAR MECHANISMS OF RENAL DEGENERATIVE PROCESSES. REGARDLESS OF THEIR INITIATING CAUSE, ALL CHRONIC KIDNEY DISEASES (CKD) DEVELOP AT SOME LEVEL ORGAN FIBROSIS THAT INTERFERES WITH KIDNEY FUNCTION. THIS IS ALSO TRUE FOR THE TWO MOST COMMON INHERITED CKD SYNDROMES, NEPHRONOPHTHITIS AND POLYCYSTIC KIDNEY DISEASE, WHOSE PRIMARY DEFECTS RESIDE WITHIN THE CILIUM OF KIDNEY EPITHELIAL CELLS. A COHORT OF ELEGANT RECENT STUDIES HAS ELICITED THE ROLE OF THE PRIMARY CILIUM AS A VERSATILE MECHANOSENSORY ORGANELLE THAT ALSO MIGHT COORDINATE CROSS-TALK BETWEEN MULTIPLE SIGNALING PATHWAYS. IN ADDITION, EPIGENETIC MECHANISMS ARE NOW REALIZED TO BE ESSENTIAL IN THE MAINTENANCE OF ADULT RENAL ARCHITECTURE. IN THIS REVIEW, WE WILL DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF THE SIGNALING SYSTEMS IMPLICATED IN KIDNEY HOMEOSTASIS AND REPAIR. 2010 17 5258 22 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 18 2211 24 EPIGENETIC MODIFICATIONS AND THE DEVELOPMENT OF KIDNEY GRAFT FIBROSIS. PURPOSE OF REVIEW: TO OUTLINE RECENT DISCOVERIES IN EPIGENETIC REGULATORY MECHANISMS THAT HAVE POTENTIAL IMPLICATIONS IN THE DEVELOPMENT OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION. RECENT FINDINGS: THE CHARACTERIZATION OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION HAS SHOWN TGFBETA/SMAD SIGNALING TO PLAY A MAJOR ROLE IN THE PROGRESSION TO CHRONIC ALLOGRAFT DYSFUNCTION. THE ONSET OF UNREGULATED PROINFLAMMATORY PATHWAYS ARE ONLY EXACERBATED BY THE DECLINE IN REGULATORY MECHANISMS LOST WITH PROGRESSIVE PATIENT AGE AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES. HOWEVER, SIGNIFICANT DEVELOPMENTS IN THE RECOGNITION OF EPIGENETIC REGULATORY MARKERS UPSTREAM OF ABERRANT TGFBETA-SIGNALING HAS SIGNIFICANT CLINICAL POTENTIAL TO PROVIDE THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL FIBROSIS. IN ADDITION, DISCOVERIES IN EXTRACELLULAR VESICLES AND THE CHARACTERIZATION OF THEIR CARGO HAS LAID NEW FRAMEWORK FOR THE POTENTIAL TO EVALUATE PATIENT OUTCOMES INDEPENDENT OF INVASIVE BIOPSIES. SUMMARY: THE CURRENT REVIEW SUMMARIZES THE MAIN FINDINGS IN EPIGENETIC MACHINERY SPECIFIC TO THE DEVELOPMENT OF RENAL FIBROSIS AND HIGHLIGHTS THERAPEUTIC OPTIONS THAT HAVE SIGNIFICANT POTENTIAL TO TRANSLATE INTO CLINICAL PRACTICE. 2021 19 2609 28 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 20 607 21 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