1 6 149 'BIOLOGIC MEMORY' IN RESPONSE TO ACUTE KIDNEY INJURY: CYTORESISTANCE, TOLL-LIKE RECEPTOR HYPER-RESPONSIVENESS AND THE ONSET OF PROGRESSIVE RENAL DISEASE. FOLLOWING THE INDUCTION OF ISCHEMIC OR TOXIN-MEDIATED ACUTE KIDNEY INJURY (AKI), CELLULAR ADAPTATIONS OCCUR THAT 'RE-PROGRAM' HOW THE KIDNEY RESPONDS TO FUTURE SUPERIMPOSED INSULTS. THIS RE-PROGRAMMING IS NOT SIMPLY A SHORT-LIVED PHENOMENON; RATHER IT CAN PERSIST FOR MANY WEEKS, IMPLYING THAT A STATE OF 'BIOLOGIC MEMORY' HAS EMERGED. THESE CHANGES CAN BE BOTH ADAPTIVE AND MALADAPTIVE IN NATURE AND THEY CAN CO-EXIST IN TIME. A BENEFICIAL ADAPTATION IS THE EMERGENCE OF ACQUIRED CYTORESISTANCE, WHEREBY A NUMBER OF PHYSIOLOGIC RESPONSES DEVELOP THAT SERVE TO PROTECT THE KIDNEY AGAINST FURTHER ISCHEMIC OR NEPHROTOXIC ATTACK. CONVERSELY, SOME CHANGES ARE MALADAPTIVE, SUCH AS A PREDISPOSITION TO GRAM-NEGATIVE OR GRAM-POSITIVE BACTEREMIA DUE TO A RENAL TUBULAR UP-REGULATION OF TOLL-LIKE RECEPTOR RESPONSES. THIS LATTER CHANGE CULMINATES IN EXAGGERATED CYTOKINE PRODUCTION, AND WITH EFFLUX INTO THE SYSTEMIC CIRCULATION, EXTRA-RENAL TISSUE INJURY CAN RESULT (SO-CALLED 'ORGAN CROSS TALK'). ANOTHER MALADAPTIVE RESPONSE IS A PERSISTENT UP-REGULATION OF PRO-INFLAMMATORY, PRO-FIBROTIC AND VASOCONSTRICTIVE GENES, CULMINATING IN PROGRESSIVE RENAL INJURY AND ULTIMATELY END-STAGE RENAL FAILURE. THE MECHANISMS BY WHICH THIS BIOLOGIC RE-PROGRAMMING, OR BIOLOGIC MEMORY, IS IMPARTED REMAIN SUBJECTS FOR CONSIDERABLE DEBATE. HOWEVER, INJURY-INDUCED, AND STABLE, EPIGENETIC REMODELING AT PRO-INFLAMMATORY/PRO-FIBROTIC GENES SEEMS LIKELY TO BE INVOLVED. THE GOAL OF THIS EDITORIAL IS TO HIGHLIGHT THAT THE SO-CALLED 'MAINTENANCE PHASE' OF ACUTE RENAL FAILURE IS NOT A STATIC ONE, SOMEWHERE BETWEEN INJURY INDUCTION AND THE ONSET OF REPAIR. RATHER, THIS PERIOD IS ONE IN WHICH THE INDUCTION OF 'BIOLOGIC MEMORY' CAN ULTIMATELY IMPACT RENAL FUNCTIONAL RECOVERY, EXTRA-RENAL INJURY AND THE POSSIBLE TRANSITION OF AKI INTO CHRONIC, PROGRESSIVE RENAL DISEASE. 2013 2 4456 30 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 3 6001 38 THE ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION: A POTENTIAL OPPORTUNITY TO IMPROVE CARE IN ACUTE KIDNEY INJURY. RECENT CONTROLLED TRIALS, EPIDEMIOLOGICAL ANALYSES AND BASIC RESEARCH STUDIES OFFER A COMPREHENSIVE VIEW OF THE SHORT AND LONG-TERM CLINICAL REPERCUSSION OF DE NOVO ACUTE KIDNEY INJURY OR AKI. WHILE MOST POST-AKI PATIENTS RECOVER THEIR BASELINE RENAL FUNCTION, A SIGNIFICANT NUMBER, APPROXIMATELY ~20% OF THOSE AFFECTED, WILL GO ON TO DEVELOP LONG TERM ILLNESS CHARACTERIZED BY AN INCREASE IN LATE STAGE CKD, CARDIOVASCULAR COMPLICATIONS, AND INCREASED DEATH RATES. WHEN AKI OCCURS IN HOSPITALIZED PATIENTS, SELECTED DEMOGRAPHIC AND LABORATORY RESULTS CAN BE INCORPORATED INTO RISK CALCULATORS THAT IDENTIFY THOSE AT HIGHER RISK FOR LONG-TERM COMPLICATIONS. THIS REVIEW TOUCHES ON SOME OF THE SALIENT EPIDEMIOLOGICAL STUDIES OF THE AKI TO CKD TRANSITION. IT ALSO FOCUSES ON CERTAIN RECENT ADVANCEMENTS IN OUR UNDERSTANDING OF THE BIOLOGICAL AND FUNCTIONAL IMPACT OF AKI ON THE RENAL TUBULE REPAIR MECHANISM, AS WELL AS THE IMPORTANT ROLE THAT GENETIC, EPIGENETIC, BIOCHEMICAL AND INFLAMMATORY EVENTS, SEEMINGLY BENEFICIAL TO THE RE-ESTABLISHMENT OF NORMAL RENAL FUNCTION, CAN BE OFFSET BY MEDIATORS OF PROGRESSIVE FIBROSIS AND IRREVERSIBLE STRUCTURAL CHANGES. CHARACTERIZATION OF BASIC PROCESSES THAT MEDIATE THE AKI TO CKD TRANSITION REVEALS PROMISING PHARMACOLOGICAL AND BIOLOGICAL AGENTS THAT HOPEFULLY WILL ONE DAY BE USED IN THE EARLY STAGES OF AKI TO PREVENT ITS DEADLY CONSEQUENCES. 2016 4 2191 42 EPIGENETIC MEMORY CONTRIBUTING TO THE PATHOGENESIS OF AKI-TO-CKD TRANSITION. EPIGENETIC MEMORY, WHICH REFERS TO THE ABILITY OF CELLS TO RETAIN AND TRANSMIT EPIGENETIC MARKS TO THEIR DAUGHTER CELLS, MAINTAINS UNIQUE GENE EXPRESSION PATTERNS. ESTABLISHING PROGRAMMED EPIGENETIC MEMORY AT EACH STAGE OF DEVELOPMENT IS REQUIRED FOR CELL DIFFERENTIATION. MOREOVER, ACCUMULATING EVIDENCE SHOWS THAT EPIGENETIC MEMORY ACQUIRED IN RESPONSE TO ENVIRONMENTAL STIMULI MAY BE ASSOCIATED WITH DIVERSE DISEASES. IN THE FIELD OF KIDNEY DISEASES, THE "MEMORY" OF ACUTE KIDNEY INJURY (AKI) LEADS TO PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD); EPIDEMIOLOGICAL STUDIES SHOW THAT PATIENTS WHO RECOVER FROM AKI ARE AT HIGH RISK OF DEVELOPING CKD. THE UNDERLYING PATHOLOGICAL PROCESSES INCLUDE NEPHRON LOSS, MALADAPTIVE EPITHELIAL REPAIR, INFLAMMATION, AND ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION. FURTHER, EPIGENETIC ALTERATIONS MAY CONTRIBUTE AS WELL TO THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION. EPIGENETIC CHANGES INDUCED BY AKI, WHICH CAN BE RECORDED IN CELLS, EXERT LONG-TERM EFFECTS AS EPIGENETIC MEMORY. CONSIDERING THE LATEST FINDINGS ON THE MOLECULAR BASIS OF EPIGENETIC MEMORY AND THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION, WE PROPOSE HERE THAT EPIGENETIC MEMORY CONTRIBUTING TO AKI-TO-CKD TRANSITION CAN BE CLASSIFIED ACCORDING TO THE PRESENCE OR ABSENCE OF PERSISTENT CHANGES IN THE ASSOCIATED REGULATION OF GENE EXPRESSION, WHICH WE DESIGNATE "DRIVING" MEMORY AND "PRIMING" MEMORY, RESPECTIVELY. "DRIVING" MEMORY, WHICH PERSISTENTLY ALTERS THE REGULATION OF GENE EXPRESSION, MAY CONTRIBUTE TO DISEASE PROGRESSION BY ACTIVATING FIBROGENIC GENES OR INHIBITING RENOPROTECTIVE GENES. THIS PROCESS MAY BE INVOLVED IN GENERATING THE PROINFLAMMATORY AND PROFIBROTIC PHENOTYPES OF MALADAPTIVELY REPAIRED TUBULAR CELLS AFTER KIDNEY INJURY. "PRIMING" MEMORY IS STORED IN SEEMINGLY SUCCESSFULLY REPAIRED TUBULAR CELLS IN THE ABSENCE OF DETECTABLE PERSISTENT PHENOTYPIC CHANGES, WHICH MAY ENHANCE A SUBSEQUENT TRANSCRIPTIONAL RESPONSE TO THE SECOND STIMULUS. THIS TYPE OF MEMORY MAY CONTRIBUTE TO AKI-TO-CKD TRANSITION THROUGH THE CUMULATIVE EFFECTS OF ENHANCED EXPRESSION OF PROFIBROTIC GENES REQUIRED FOR WOUND REPAIR AFTER RECURRENT AKI. FURTHER UNDERSTANDING OF EPIGENETIC MEMORY WILL IDENTIFY THERAPEUTIC TARGETS OF FUTURE EPIGENETIC INTERVENTION TO PREVENT AKI-TO-CKD TRANSITION. 2022 5 1487 29 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 6 859 27 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 4719 29 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 8 4204 34 METABOLISM, EPIGENETICS, AND CAUSAL INFERENCE IN HEART FAILURE. EUKARYOTES MUST BALANCE THE METABOLIC AND CELL DEATH ACTIONS OF MITOCHONDRIA VIA CONTROL OF GENE EXPRESSION AND CELL FATE BY CHROMATIN, THEREBY FUNCTIONALLY BINDING THE METABOLOME AND EPIGENOME. THIS INTERACTION HAS FAR-REACHING IMPLICATIONS FOR CHRONIC DISEASES IN HUMANS, THE MOST COMMON OF WHICH ARE THOSE OF THE CARDIOVASCULAR SYSTEM. THE MOST DEVASTATING CONSEQUENCE OF CARDIOVASCULAR DISEASE, HEART FAILURE, IS NOT A SINGLE DISEASE, DIAGNOSIS, OR ENDPOINT. HUMAN AND ANIMAL STUDIES HAVE REVEALED THAT, REGARDLESS OF ETIOLOGY AND SYMPTOMS, HEART FAILURE IS UNIVERSALLY ASSOCIATED WITH ABNORMAL METABOLISM AND GENE EXPRESSION - TO FRAME THIS AS CAUSE OR CONSEQUENCE, HOWEVER, MAY BE TO WRONGFOOT THE QUESTION. THIS ESSAY AIMS TO CHALLENGE CURRENT THINKING ON METABOLIC-EPIGENETIC CROSSTALK IN HEART FAILURE, PRESENTING HYPOTHESES FOR HOW CHRONIC DISEASES ARISE, TAKE HOLD, AND PERSIST. WE UNPACK ASSUMPTIONS ABOUT THE ORDER OF OPERATIONS FOR GENE EXPRESSION AND METABOLISM, EXPLORING RECENT FINDINGS IN NONCARDIAC SYSTEMS THAT LINK METABOLIC INTERMEDIATES DIRECTLY TO CHROMATIN REMODELING. LASTLY, WE DISCUSS POTENTIAL MECHANISMS BY WHICH CHROMATIN MAY SERVE AS A SUBSTRATE FOR METABOLIC MEMORY, AND HOW CHANGES IN CELLULAR TRANSCRIPTOMES (AND HENCE IN CELLULAR BEHAVIOR) IN RESPONSE TO STRESS CORRESPOND TO GLOBAL CHANGES IN CHROMATIN ACCESSIBILITY AND STRUCTURE. 2020 9 6129 31 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 10 2592 25 EPIGENETICS OF RENAL DEVELOPMENT AND DISEASE. AN UNDERSTANDING OF EPIGENETICS IS INDISPENSABLE TO OUR UNDERSTANDING OF GENE REGULATION UNDER NORMAL AND PATHOLOGICAL STATES. THIS KNOWLEDGE WILL HELP WITH DESIGNING BETTER THERAPEUTIC APPROACHES IN REGENERATIVE TISSUE MEDICINE. EPIGENETICS ALLOWS US TO PARSE OUT THE MECHANISMS BY WHICH TRANSCRIPTIONAL REGULATORS GAIN ACCESS TO SPECIFIC GENE LOCI THEREBY IMPRINTING EPIGENETIC INFORMATION AFFECTING CHROMATIN FUNCTION. THIS EPIGENETIC MEMORY FORMS THE BASIS OF CELL LINEAGE SPECIFICATION IN MULTICELLULAR ORGANISMS. POST-TRANSLATIONAL MODIFICATIONS TO DNA AND HISTONES IN THE NUCLEOSOME CORE FORM CHARACTERISTIC EPIGENETIC CODES WHICH ARE DISTINCT FOR SELF-RENEWING AND PRIMED PROGENITOR CELL POPULATIONS. STUDIES OF CHROMATIN MODIFIERS AND MODIFICATIONS IN RENAL DEVELOPMENT AND DISEASE HAVE BEEN GAINING MOMENTUM. BOTH CONGENITAL AND ADULT RENAL DISEASES HAVE A GENE-ENVIRONMENT COMPONENT, WHICH INVOLVES ALTERATIONS TO THE EPIGENETIC INFORMATION IMPRINTED DURING DEVELOPMENT. THIS EPIGENETIC MEMORY MUST BE CHARACTERIZED TO ESTABLISH OPTIMAL TREATMENT OF BOTH ACUTE AND CHRONIC RENAL DISEASES. 2016 11 221 41 ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. BACKGROUND: ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY RENAL RECOVERY, IS A RISK FACTOR FOR THE FUTURE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD). IN THE PREVIOUS YEARS, NOVEL INSIGHTS IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION SUGGESTED A CAUSAL LINK BETWEEN AKI AND CKD DUE TO A MALADAPTIVE REPAIR AFTER SEVERE AND REPEATED INJURY. SUMMARY: SEVERAL PATHOLOGICAL MECHANISMS HAVE BEEN PROPOSED TO CONTRIBUTE TO THE PROGRESSION OF AKI AND TRANSITION TO CKD/ESRD INCLUDING HYPOXIA AND MICROVASCULAR RAREFACTION, ALTERATIONS OF RENAL RESIDENT CELL PHENOTYPES AND FUNCTIONS, CELL CYCLE ARREST IN THE G2/M PHASE, PERSISTENT CHRONIC INFLAMMATION, AND DEVELOPMENT OF INTERSTITIAL FIBROSIS, MITOCHONDRIAL FRAGMENTATION, EPIGENETIC CHANGES, ACTIVATION OF RENIN-ANGIOTENSIN SYSTEM (RAS), CELL AND TISSUE SENESCENCE. FURTHERMORE, SEVERAL CLINICAL FACTORS HAVE BEEN IDENTIFIED SUCH AS SEVERITY OF AKI, AGE, AND COMORBIDITIES. THE IDENTIFICATION OF AKI-TO-CKD BIOMARKERS COULD IMPROVE THE EARLY IDENTIFICATION OF AKI PATIENTS WITH HIGHER RISK FOR CKD PROGRESSION. HOWEVER, ALTHOUGH OUR UNDERSTANDING IN THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION IS SIGNIFICANTLY IMPROVED, NO NOVEL INTERVENTION HAS BEEN VALIDATED. POTENTIAL THERAPEUTIC APPROACHES TO TREAT AKI AND BLOCK THE TRANSITION TO CKD/ESRD HAVE BEEN RECENTLY REPORTED, BUT THEY NEED FURTHER VALIDATIONS. KEY MESSAGES: MALADAPTIVE REPAIR AFTER AKI IS STRONGLY ASSOCIATED TO THE DEVELOPMENT OF CKD AND LONG-TERM CONSEQUENCES. THE PROMPT IDENTIFICATION OF PATIENTS AT HIGHER RISK FOR LATE CKD PROGRESSION AND THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS REMAIN CRITICAL RESEARCH GOALS. 2018 12 3418 31 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 13 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 14 2193 33 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 15 2807 26 FETAL PROGRAMMING OF CHRONIC KIDNEY DISEASE: THE ROLE OF MATERNAL SMOKING, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC MODFIFICATION. THE ROLE OF AN ADVERSE IN UTERO ENVIRONMENT IN THE PROGRAMMING OF CHRONIC KIDNEY DISEASE IN THE ADULT OFFSPRING IS INCREASINGLY RECOGNIZED. THE CELLULAR AND MOLECULAR MECHANISMS LINKING THE IN UTERO ENVIRONMENT AND FUTURE DISEASE SUSCEPTIBILITY REMAIN UNKNOWN. MATERNAL SMOKING IS A COMMON MODIFIABLE ADVERSE IN UTERO EXPOSURE, POTENTIALLY ASSOCIATED WITH BOTH MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC MODIFICATION IN THE OFFSPRING. WHILE STUDIES ARE EMERGING THAT POINT TOWARD A KEY ROLE OF MITOCHONDRIAL DYSFUNCTION IN ACUTE AND CHRONIC KIDNEY DISEASE, IT MAY HAVE ITS ORIGIN IN EARLY DEVELOPMENT, BECOMING CLINICALLY APPARENT WHEN SECONDARY INSULTS OCCUR. ABERRANT EPIGENETIC PROGRAMMING MAY ADD AN ADDITIONAL LAYER OF COMPLEXITY TO ORCHESTRATE FIBROGENESIS IN THE KIDNEY AND SUSCEPTIBILITY TO CHRONIC KIDNEY DISEASE IN LATER LIFE. IN THIS REVIEW, WE EXPLORE THE EVIDENCE FOR MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC MODIFICATION THROUGH ABERRANT DNA METHYLATION AS KEY MECHANISTIC ASPECTS OF FETAL PROGRAMMING OF CHRONIC KIDNEY DISEASE AND DISCUSS THEIR POTENTIAL USE IN DIAGNOSTICS AND TARGETS FOR THERAPY. 2015 16 3988 23 LONG-TERM WINDOW OF ISCHEMIC TOLERANCE: AN EVOLUTIONARILY CONSERVED FORM OF METABOLIC PLASTICITY REGULATED BY EPIGENETIC MODIFICATIONS? IN THE ABSENCE OF EFFECTIVE NEUROPROTECTIVE AGENTS IN THE CLINIC, ISCHEMIC AND PHARMACOLOGICAL PRECONDITIONING ARE GAINING INCREASED INTEREST IN THE FIELD OF CEREBRAL ISCHEMIA. OUR LAB RECENTLY REPORTED THAT RESVERATROL PRECONDITIONING AFFORDS TOLERANCE AGAINST A FOCAL CEREBRAL ISCHEMIC INSULT IN MICE THAT CAN LAST FOR AT LEAST 14 DAYS IN VIVO MAKING IT THE LONGEST WINDOW OF ISCHEMIC TOLERANCE DISCOVERED TO DATE BY A SINGLE ADMINISTRATION OF A PHARMACOLOGICAL AGENT. THE MECHANISM BEHIND THIS NOVEL EXTENDED WINDOW OF ISCHEMIC TOLERANCE REMAINS ELUSIVE. IN THE BELOW COMMENTARY WE DISCUSS POTENTIAL MECHANISMS THAT COULD EXPLAIN THIS NOVEL EXTENDED WINDOW OF ISCHEMIC TOLERANCE IN THE CONTEXT OF PREVIOUSLY IDENTIFIED WINDOWS AND THE KNOWN MECHANISMS BEHIND THEM. WE ALSO DRAW PARALLELS FROM THE FIELDS OF HIBERNATION AND HYPOXIA-TOLERANCE, WHICH ARE CHRONIC ADAPTATIONS TO SEVERE CONDITIONS OF HYPOXIA AND ISCHEMIA KNOWN TO BE MEDIATED BY A FORM OF METABOLIC DEPRESSION. WE ALSO BRIEFLY DISCUSS THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN MAINTAINING THIS DEPRESSED STATE OF METABOLISM. 2016 17 6308 32 THE REGULATION OF APOPTOSIS IN KIDNEY DEVELOPMENT: IMPLICATIONS FOR NEPHRON NUMBER AND PATTERN? APOPTOSIS IS ESSENTIAL TO REMODEL DEVELOPING STRUCTURES AND ELIMINATE SUPERFLUOUS CELLS IN A CONTROLLED MANNER DURING NORMAL DEVELOPMENT, AND CONTINUES TO BE AN IMPORTANT COMPONENT OF TISSUE REMODELING AND REGENERATION DURING AN ORGANISM'S LIFESPAN, OR AS A RESPONSE TO INJURY. THIS MINI REVIEW WILL DISCUSS RECENT STUDIES THAT HAVE PROVIDED INSIGHTS INTO THE ROLES OF APOPTOSIS IN THE DETERMINATION OF NEPHRON NUMBER AND PATTERN, DURING NORMAL AND ABNORMAL KIDNEY DEVELOPMENT. THE REGULATION OF CONGENITAL NEPHRON ENDOWMENT HAS IMPLICATIONS FOR RISK OF CHRONIC KIDNEY DISEASE IN LATER LIFE, WHEREAS ABNORMALITIES IN NEPHRON PATTERN ARE ASSOCIATED WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (THE LEADING CAUSE OF RENAL DISEASE IN CHILDREN). TIGHT REGULATION OF APOPTOSIS IS REQUIRED IN NORMAL RENAL MORPHOGENESIS, ALTHOUGH MANY QUESTIONS REMAIN REGARDING THE REGULATION OF APOPTOSIS BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS, IN ADDITION TO THE FUNCTIONAL REQUIREMENT OF DIFFERENT COMPONENTS OF THE APOPTOTIC PATHWAY. 2014 18 1515 30 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 19 3123 32 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 20 5258 37 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