1 3856 117 ISCHAEMIA REPERFUSION INJURY: MECHANISMS OF PROGRESSION TO CHRONIC GRAFT DYSFUNCTION. THE INCREASING USE OF EXTENDED CRITERIA ORGANS TO MEET THE DEMAND FOR KIDNEY TRANSPLANTATION RAISES AN IMPORTANT QUESTION OF HOW THE SEVERITY OF EARLY ISCHAEMIC INJURY INFLUENCES LONG-TERM OUTCOMES. SIGNIFICANT ACUTE ISCHAEMIC KIDNEY INJURY IS ASSOCIATED WITH DELAYED GRAFT FUNCTION, INCREASED IMMUNE-ASSOCIATED EVENTS AND, ULTIMATELY, EARLIER DETERIORATION OF GRAFT FUNCTION. A COMPREHENSIVE UNDERSTANDING OF IMMEDIATE MOLECULAR EVENTS THAT ENSUE POST-ISCHAEMIA AND THEIR POTENTIAL LONG-TERM CONSEQUENCES ARE KEY TO THE DISCOVERY OF NOVEL THERAPEUTIC TARGETS. ACUTE ISCHAEMIC INJURY PRIMARILY AFFECTS TUBULAR STRUCTURE AND FUNCTION. DEPENDING ON THE SEVERITY AND PERSISTENCE OF THE INSULT, THIS MAY RESOLVE COMPLETELY, LEADING TO RESTORATION OF NORMAL FUNCTION, OR BE SUSTAINED, RESULTING IN PERSISTENT RENAL IMPAIRMENT AND PROGRESSIVE FUNCTIONAL LOSS. LONG-TERM EFFECTS OF ACUTE RENAL ISCHAEMIA ARE MEDIATED BY SEVERAL MECHANISMS INCLUDING HYPOXIA, HIF-1 ACTIVATION, ENDOTHELIAL DYSFUNCTION LEADING TO VASCULAR RAREFACTION, SUSTAINED PRO-INFLAMMATORY STIMULI INVOLVING INNATE AND ADAPTIVE IMMUNE RESPONSES, FAILURE OF TUBULAR CELLS TO RECOVER AND EPIGENETIC CHANGES. THIS REVIEW DESCRIBES THE BIOLOGICAL RELEVANCE AND INTERACTION OF THESE MECHANISMS BASED ON CURRENTLY AVAILABLE EVIDENCE. 2019 2 5420 36 REGULATION OF HYPOXIA-INDUCIBLE FACTOR IN KIDNEY DISEASE. HYPOXIA PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY (AKI) AND PRESUMABLY ALSO CHRONIC KIDNEY DISEASE (CKD). HYPOXIA-INDUCIBLE FACTOR (HIF) IS THE MASTER TRANSCRIPTION FACTOR THAT REGULATES ADAPTIVE RESPONSES AGAINST HYPOXIA. UNDER HYPOXIC CONDITIONS, HIF ACTIVATES TARGET GENES WITH HYPOXIA-RESPONSIVE ELEMENTS IN THEIR REGULATORY REGIONS. THE HIF ISOFORMS AND REGULATORS OF HIF (I.E. PROLYL HYDROXYLASES) SHOW CELL TYPE-SPECIFIC DISTRIBUTIONS. HYPOXIA IS OBSERVED IN BOTH ISCHAEMIC AND SO-CALLED NON-ISCHAEMIC FORMS OF AKI. IN ADDITION TO THE ACUTE PHASE, HYPOXIA MAY ENSUE DURING THE RECOVERY PHASE OF AKI, POSSIBLY DUE TO THE OXYGEN-CONSUMING PROCESSES OF CELL GROWTH AND PROLIFERATION FOR REPAIR. ALTHOUGH HIF PROTECTS THE KIDNEY AGAINST AKI, INTRINSIC HIF ACTIVATION IS SUBMAXIMAL IN AKI AND FURTHER AUGMENTATION OF HIF AMELIORATES DISEASE MANIFESTATIONS. THE KIDNEY IN CKD ALSO SUFFERS FROM HYPOXIA CAUSED BY MULTIPLE MECHANISMS, INCLUDING SUSTAINED OXYGEN DEMANDS IN THE REMAINING NEPHRONS DUE TO MALADAPTIVE TUBULOGLOMERULAR FEEDBACK. WHETHER HIF IS CHRONICALLY UPREGULATED IN CKD IS CONTENTIOUS. HYPOXIA-INDUCIBLE FACTOR ACTIVATION IS A PROMISING THERAPEUTIC APPROACH TO CKD, BUT EXCESSIVE ACTIVATION OF HIF MAY BE DELETERIOUS. IT IS LIKELY THAT THERE IS A THERAPEUTIC WINDOW OF HIF ACTIVATION IN CHRONIC CONDITIONS. UNDER CERTAIN CIRCUMSTANCES, ANIMALS WITH CKD ARE PROTECTED AGAINST AKI AND THIS MAY BE EXPLAINED BY NON-PHYSIOLOGICAL HYPOXIA OF THE KIDNEY AND SUBSEQUENT HIF EXPRESSION. IN ADDITION, AN ACUTE HYPOXIC INSULT MAY INDUCE LONG-LASTING CHANGES, POSSIBLY INCLUDING EPIGENETIC MODIFICATIONS INDUCED BY HIF. THESE OBSERVATIONS SUGGEST A COMPLEX INTERACTION BETWEEN AKI AND CKD VIA HYPOXIA AND HIF ACTIVATION. 2013 3 5891 23 SYSTEMS BIOLOGY IN CHRONIC HEART FAILURE-IDENTIFICATION OF POTENTIAL MIRNA REGULATORS. HEART FAILURE (HF) IS A COMPLEX DISEASE ENTITY WITH HIGH CLINICAL IMPACT, POORLY UNDERSTOOD PATHOPHYSIOLOGY AND SCANTLY KNOWN MIRNA-MEDIATED EPIGENETIC REGULATION. WE HAVE ANALYSED MIRNA PATTERNS IN PATIENTS WITH CHRONIC HF (CHF) AND A SEX- AND AGE-MATCHED REFERENCE GROUP AND PURSUED AN IN SILICO SYSTEM BIOLOGY ANALYSIS TO DISCERN PATHWAYS INVOLVED IN CHF PATHOPHYSIOLOGY. TWENTY-EIGHT MIRNAS WERE IDENTIFIED IN CHF THAT WERE UP-REGULATED IN THE REFERENCE GROUP, AND EIGHT OF THEM WERE VALIDATED BY RT-QPCR. IN SILICO ANALYSIS OF PREDICTED TARGETS BY STRING PROTEIN-PROTEIN INTERACTION NETWORKS REVEALED EIGHT CLUSTER NETWORKS (INVOLVING SEVEN OF THE IDENTIFIED MIRNAS) ENRICHED IN PATHWAYS RELATED TO CELL CYCLE, RAS, CHEMOKINE, PI3K-AKT AND TGF-BETA SIGNALING. BY ROC CURVE ANALYSIS, COMBINED PROBABILITIES OF THESE SEVEN MIRNAS (LET-7A-5P, MIR-107, MIR-125A-5P, MIR-139-5P, MIR-150-5P, MIR-30B-5P AND MIR-342-3P; CLUSTERS 1-4 [C:1-4]), DISCRIMINATED BETWEEN HF WITH PRESERVED EJECTION FRACTION (HFPEF) AND HF WITH REDUCED EJECTION FRACTION (HFREF), AND ISCHAEMIC AND NON-ISCHAEMIC AETIOLOGY. A COMBINATION OF MIR-107, MIR-139-5P AND MIR-150-5P, INVOLVED IN CLUSTERS 5 AND 7 (C:5+7), DISCRIMINATED HFPEF FROM HFREF. PATHWAY ENRICHMENT ANALYSIS OF MIRNAS PRESENT IN C:1-4 (LET-7A-5P, MIR-125A-5P, MIR-30B-5P AND MIR-342-3P) REVEALED PATHWAYS RELATED TO HF PATHOGENESIS. IN CONCLUSION, WE HAVE IDENTIFIED A DIFFERENTIAL SIGNATURE OF DOWN-REGULATED MIRNAS IN THE PLASMA OF HF PATIENTS AND PROPOSE NOVEL CELLULAR MECHANISMS INVOLVED IN CHF PATHOGENESIS. 2022 4 3048 24 GENOME-WIDE ANALYSIS REVEALED THAT DZNEP REDUCES TUBULOINTERSTITIAL FIBROSIS VIA DOWN-REGULATION OF PRO-FIBROTIC GENES. TUBULOINTERSTITIAL FIBROSIS HAS BEEN RECENTLY REPORTED TO BE CAUSED BY THE COLLAPSE OF THE EPIGENETIC REGULATION OF KIDNEY DISEASES. WE EXAMINED WHETHER PHARMACOLOGICAL INHIBITION OF HISTONE MODIFICATION IS EFFECTIVE AGAINST RENAL FIBROSIS. DZNEP (3-DEAZANEPLANOCIN A) WAS ORIGINALLY DEVELOPED AS AN ANTI-CANCER DRUG TO INHIBIT THE REPRESSIVE HISTONE MARK, H3K27ME3. WE USED A MODEL OF CHRONIC TUBULOINTERSTITIAL FIBROSIS INDUCED BY UNILATERAL ISCHAEMIA/REPERFUSION AND ADMINISTERED DZNEP INTRAVENOUSLY TO THE MICE FOR 8 WEEKS. WE FOUND DZNEP CONTRIBUTES TO THE REDUCTION OF TUBULOINTERSTITIAL FIBROSIS. WE SELECTED ONLY TUBULAR CELLS FROM IN VIVO SAMPLES USING LASER-CAPTURE MICRODISSECTION BECAUSE EPIGENETIC REGULATION IS SPECIFIC TO THE CELL TYPES, AND WE FOCUSED ON THE CHANGES IN THE TUBULAR CELLS. WE PERFORMED A GENOME-WIDE ANALYSIS OF TUBULAR CELLS USING HIGH-THROUGHPUT SEQUENCING (RNA-SEQ) TO IDENTIFY NOVEL EPIGENETIC FACTORS ASSOCIATED WITH RENAL FIBROSIS. WE FOUND THAT PRO-FIBROTIC GENES SUCH AS COL3A1 (COLLAGEN TYPE 3A1) AND TIMP2 (TISSUE INHIBITOR OF METALLOPROTEINASE 2) WERE SUPPRESSED BY DZNEP IN VIVO. IN ADDITION, PRO-FIBROTIC GENES SUCH AS COL4A1 (COLLAGEN TYPE 4A1), TIMP2 AND MMP14 WERE DOWN-REGULATED BY DZNEP IN VITRO. IN CONCLUSION, WE FOUND THAT PHARMACOLOGICAL EPIGENETIC MODIFICATION BY DZNEP DECREASED THE EXPRESSION LEVELS OF FIBROGENIC GENES IN TUBULAR CELLS AND INHIBITED TUBULOINTERSTITIAL FIBROSIS. 2018 5 6051 35 THE CONTRIBUTION OF HISTONE CROTONYLATION TO TISSUE HEALTH AND DISEASE: FOCUS ON KIDNEY HEALTH. ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD) ARE THE MOST SEVERE CONSEQUENCES OF KIDNEY INJURY. THEY ARE INTERCONNECTED SYNDROMES AS CKD PREDISPOSES TO AKI AND AKI MAY ACCELERATE CKD PROGRESSION. DESPITE THEIR GROWING IMPACT ON THE GLOBAL BURDEN OF DISEASE, THERE IS NO SATISFACTORY TREATMENT FOR AKI AND CURRENT THERAPEUTIC APPROACHES TO CKD REMAIN SUBOPTIMAL. RECENT RESEARCH HAS FOCUSED ON THE THERAPEUTIC TARGET POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION, INCLUDING NON-CODING RNAS AND THE COVALENT MODIFICATIONS OF HISTONES AND DNA. INDEED, SEVERAL DRUGS TARGETING HISTONE MODIFICATIONS ARE IN CLINICAL USE OR UNDERGOING CLINICAL TRIALS. ACYL-LYSINE HISTONE MODIFICATIONS (E.G. METHYLATION, ACETYLATION, AND CROTONYLATION) HAVE MODULATED EXPERIMENTAL KIDNEY INJURY. MOST RECENTLY, INCREASED HISTONE LYSINE CROTONYLATION (KCR) WAS OBSERVED DURING EXPERIMENTAL AKI AND COULD BE REPRODUCED IN CULTURED TUBULAR CELLS EXPOSED TO INFLAMMATORY STRESS TRIGGERED BY THE CYTOKINE TWEAK. THE DEGREE OF KIDNEY HISTONE CROTONYLATION WAS MODULATED BY CROTONATE AVAILABILITY AND CROTONATE SUPPLEMENTATION PROTECTED FROM NEPHROTOXIC AKI. WE NOW REVIEW THE FUNCTIONAL RELEVANCE OF HISTONE CROTONYLATION IN KIDNEY DISEASE AND OTHER PATHOPHYSIOLOGICAL CONTEXTS, AS WELL AS THE IMPLICATIONS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES. THESE STUDIES PROVIDE INSIGHTS INTO THE OVERALL ROLE OF HISTONE CROTONYLATION IN HEALTH AND DISEASE. 2020 6 2385 28 EPIGENETIC REGULATORS OF THE REVASCULARIZATION RESPONSE TO CHRONIC ARTERIAL OCCLUSION. PERIPHERAL ARTERIAL DISEASE (PAD) IS THE LEADING CAUSE OF LOWER LIMB AMPUTATION AND ESTIMATED TO AFFECT OVER 202 MILLION PEOPLE WORLDWIDE. PAD IS CAUSED BY ATHEROSCLEROTIC LESIONS THAT OCCLUDE LARGE ARTERIES IN THE LOWER LIMBS, LEADING TO INSUFFICIENT BLOOD PERFUSION OF DISTAL TISSUES. GIVEN THE SEVERITY OF THIS CLINICAL PROBLEM, THERE HAS BEEN LONG-STANDING INTEREST IN BOTH UNDERSTANDING HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE AND VASCULATURE AND IDENTIFYING THERAPEUTIC APPROACHES CAPABLE OF RESTORING TISSUE COMPOSITION AND VASCULAR FUNCTION TO A HEALTHY STATE. TO DATE, THE MOST WIDELY UTILIZED ANIMAL MODEL FOR PERFORMING SUCH STUDIES HAS BEEN THE ISCHAEMIC MOUSE HINDLIMB. DESPITE NOT BEING A MODEL OF PAD PER SE, THE ISCHAEMIC HINDLIMB MODEL DOES RECAPITULATE SEVERAL KEY ASPECTS OF PAD. FURTHER, IT HAS SERVED AS A VALUABLE PLATFORM UPON WHICH WE HAVE BUILT MUCH OF OUR UNDERSTANDING OF HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE COMPOSITION, MUSCLE REGENERATION AND ANGIOGENESIS, AND COLLATERAL ARTERIOGENESIS. RECENTLY, THERE HAS BEEN A GLOBAL SURGE IN RESEARCH AIMED AT UNDERSTANDING HOW GENE EXPRESSION IS REGULATED BY EPIGENETIC FACTORS (I.E. NON-CODING RNAS, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND DNA METHYLATION). THUS, PERHAPS NOT UNEXPECTEDLY, MANY RECENT STUDIES HAVE IDENTIFIED ESSENTIAL ROLES FOR EPIGENETIC FACTORS IN REGULATING KEY RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S). IN THIS REVIEW, WE SUMMARIZE THE MECHANISMS OF ACTION OF THESE EPIGENETIC REGULATORS AND HIGHLIGHT SEVERAL RECENT STUDIES INVESTIGATING THE ROLE OF SAID REGULATORS IN THE CONTEXT OF HINDLIMB ISCHAEMIA. IN ADDITION, WE FOCUS ON HOW THESE RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF EPIGENETICS IN REGULATING RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S) CAN INFORM FUTURE THERAPEUTIC APPLICATIONS TO PROMOTE REVASCULARIZATION AND PERFUSION RECOVERY IN THE SETTING OF PAD. 2019 7 5925 37 TARGETING EPIGENETIC DNA AND HISTONE MODIFICATIONS TO TREAT KIDNEY DISEASE. EPIGENETICS REFERS TO HERITABLE CHANGES IN GENE EXPRESSION PATTERNS NOT CAUSED BY AN ALTERED NUCLEOTIDE SEQUENCE, AND INCLUDES NON-CODING RNAS AND COVALENT MODIFICATIONS OF DNA AND HISTONES. THIS REVIEW FOCUSES ON FUNCTIONAL EVIDENCE FOR THE INVOLVEMENT OF DNA AND HISTONE EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF KIDNEY DISEASE AND THE POTENTIAL THERAPEUTIC IMPLICATIONS. THERE IS EVIDENCE OF ACTIVATION OF EPIGENETIC REGULATORY MECHANISMS IN ACUTE KIDNEY INJURY (AKI), CHRONIC KIDNEY DISEASE (CKD) AND THE AKI-TO-CKD TRANSITION OF DIVERSE AETIOLOGIES, INCLUDING ISCHAEMIA-REPERFUSION INJURY, NEPHROTOXICITY, URETERAL OBSTRUCTION, DIABETES, GLOMERULONEPHRITIS AND POLYCYSTIC KIDNEY DISEASE. A BENEFICIAL IN VIVO EFFECT OVER PRECLINICAL KIDNEY INJURY HAS BEEN REPORTED FOR DRUGS THAT DECREASE DNA METHYLATION BY EITHER INHIBITING DNA METHYLATION (E.G. 5-AZACYTIDINE AND DECITABINE) OR ACTIVATING DNA DEMETHYLATION (E.G. HYDRALAZINE), DECREASE HISTONE METHYLATION BY INHIBITING HISTONE METHYLTRANSFERASES, INCREASE HISTONE ACETYLATION BY INHIBITING HISTONE DEACETYLASES (HDACS, E.G. VALPROIC ACID, VORINOSTAT, ENTINOSTAT), INCREASE HISTONE CROTONYLATION (CROTONATE) OR INTERFERE WITH HISTONE MODIFICATION READERS [E.G. INHIBITS OF BROMODOMAIN AND EXTRA-TERMINAL PROTEINS (BET)]. MOST PRECLINICAL STUDIES ADDRESSED CKD OR THE AKI-TO-CKD TRANSITION. CROTONATE ADMINISTRATION PROTECTED FROM NEPHROTOXIC AKI, BUT EVIDENCE IS CONFLICTING ON DNA METHYLATION INHIBITORS FOR PRECLINICAL AKI. SEVERAL DRUGS TARGETING EPIGENETIC REGULATORS ARE IN CLINICAL DEVELOPMENT OR USE, MOST OF THEM FOR MALIGNANCY. THE BET INHIBITOR APABETALONE IS IN PHASE 3 TRIALS FOR ATHEROSCLEROSIS, KIDNEY FUNCTION BEING A SECONDARY ENDPOINT, BUT NEPHROTOXICITY WAS REPORTED FOR DNA AND HDAC INHIBITORS. WHILE RESEARCH INTO EPIGENETIC MODULATORS MAY PROVIDE NOVEL THERAPIES FOR KIDNEY DISEASE, CAUTION SHOULD BE EXERCISED BASED ON THE CLINICAL NEPHROTOXICITY OF SOME DRUGS. 2018 8 2034 25 EPIGENETIC CHANGES IN THE ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. PREVIOUSLY ACUTE KIDNEY INJURY (AKI) HAD BEEN BELIEVED TO BE A TRANSIENT EVENT, AND RECOVERY FROM AKI HAD BEEN THOUGHT TO LEAD TO NO CONSEQUENCES. HOWEVER, RECENT EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT EVEN IF THERE IS COMPLETE RECOVERY OF THE KIDNEY FUNCTION, AKI CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD) AND EVENTUALLY IN END-STAGE KIDNEY DISEASE IN THE LONG TERM. TRANSITION OF AKI TO CKD IS MEDIATED BY MULTIPLE MECHANISMS, INCLUDING ABERRANT CELL CYCLE ARREST AND HYPOXIA. HYPOXIA OF THE KIDNEY IS INDUCED BY RAREFACTION OF THE PERITUBULAR CAPILLARIES AFTER AKI EPISODES, AND INDUCES INFLAMMATION AND FIBROSIS. IT SHOULD ALSO BE NOTED THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO HYPOXIA, AND EPIGENETIC CHANGES INDUCED BY HYPOXIA, CALLED "HYPOXIC MEMORY" CAN EXPLAIN THE AKI-TO-CKD TRANSITION IN THE LONG TERM AFTER COMPLETE RECOVERY FROM THE INITIAL AKI EPISODE. TARGETING HYPOXIA AND SUBSEQUENT EPIGENETIC CHANGES ARE PROMISING STRATEGIES TO BLOCK THE TRANSITION FROM AKI TO CKD. 2017 9 1250 25 CURRENT PERSPECTIVES ON MITOCHONDRIAL DYSFUNCTION IN MIGRAINE. MITOCHONDRIA ARE AN AUTONOMOUS ORGANELLE THAT PLAYS A CRUCIAL ROLE IN THE METABOLIC ASPECTS OF A CELL. CORTICAL SPREADING DEPRESSION (CSD) AND FLUCTUATIONS IN THE CEREBRAL BLOOD FLOW HAVE FOR LONG BEEN MECHANISMS UNDERLYING MIGRAINE. IT IS A NEUROVASCULAR DISORDER WITH A UNILATERAL MANIFESTATION OF DISTURBING, THROBBING AND PULSATING HEAD PAIN. MIGRAINE AFFECTS 2.6% AND 21.7% OF THE GENERAL POPULATION AND IS THE MAJOR CAUSE OF PARTIAL DISABILITY IN THE AGE GROUP 15-49. HIGHER MUTATION RATES, IMBALANCE IN CONCENTRATION OF PHYSIOLOGICALLY RELEVANT MOLECULES AND OXIDATIVE STRESS BIOMARKERS HAVE BEEN THE MAIN THEMES OF DISCUSSION IN DETERMINING THE ROLE OF MITOCHONDRIAL DISABILITY IN MIGRAINE. THE CORRELATION OF MIGRAINE WITH OTHER DISORDERS LIKE HEMIPLEGIC MIGRAINE; MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS AND STROKE-LIKE EPISODES [MELAS]; TENSION-TYPE HEADACHE (TTH); CYCLIC VOMITING SYNDROME (CVS), ISCHAEMIC STROKE; AND HYPERTENSION HAS HELPED IN THE ASSESSMENT OF THE PHYSIOLOGICAL AND MORPHOGENETIC BASIS OF MIGRAINE. HERE, WE HAVE REVIEWED THE DIFFERENT NUANCES OF MITOCHONDRIAL DYSFUNCTION AND MIGRAINE. THE DIFFERENT MTDNA POLYMORPHISMS THAT CAN AFFECT THE GENERATION AND TRANSMISSION OF NERVE IMPULSE HAS BEEN HIGHLIGHTED AND SUPPORTED WITH RESEARCH FINDINGS. IN ADDITION TO THIS, THE GENETIC BASIS OF MIGRAINE PATHOGENESIS AS A CONSEQUENCE OF MUTATIONS IN NUCLEAR DNA THAT CAN, IN TURN, AFFECT THE SYNTHESIS OF DEFECTIVE MITOCHONDRIAL PROTEINS IS DISCUSSED ALONG WITH A BRIEF OVERVIEW OF EPIGENETIC PROFILE. THIS REVIEW GIVES AN OVERVIEW OF THE PATHOPHYSIOLOGY OF MIGRAINE AND EXPLORES MITOCHONDRIAL DYSFUNCTION AS A POTENTIAL UNDERLYING MECHANISM. ALSO, THERAPEUTIC SUPPLEMENTS FOR MANAGING MIGRAINE HAVE BEEN DISCUSSED AT DIFFERENT JUNCTURES IN THIS PAPER. 2022 10 4513 28 MULTI-OMIC APPROACHES TO ACUTE KIDNEY INJURY AND REPAIR. THE KIDNEY HAS A REMARKABLE REGENERATIVE CAPACITY. IN RESPONSE TO ISCHEMIC OR TOXIC INJURY, PROXIMAL TUBULE CELLS CAN PROLIFERATE TO REBUILD DAMAGED TUBULES AND RESTORE KIDNEY FUNCTION. HOWEVER, SEVERE ACUTE KIDNEY INJURY (AKI) OR RECURRENT AKI EVENTS CAN LEAD TO MALADAPTIVE REPAIR AND DISEASE PROGRESSION FROM AKI TO CHRONIC KIDNEY DISEASE (CKD). THE APPLICATION OF SINGLE CELL TECHNOLOGIES HAS IDENTIFIED INJURED PROXIMAL TUBULE CELL STATES WEEKS AFTER AKI, DISTINGUISHED BY A PRO-INFLAMMATORY SENESCENT MOLECULAR SIGNATURE. EPIGENETIC STUDIES HIGHLIGHTED DYNAMIC CHANGES IN THE CHROMATIN LANDSCAPE OF THE KIDNEY FOLLOWING AKI AND DESCRIBED KEY TRANSCRIPTION FACTORS LINKED TO THE AKI RESPONSE. THE INTEGRATION OF MULTI-OMIC TECHNOLOGIES OPENS NEW POSSIBILITIES TO IMPROVE OUR UNDERSTANDING OF AKI AND THE DRIVING FORCES BEHIND THE AKI-TO-CKD TRANSITION, WITH THE ULTIMATE GOAL OF DESIGNING TAILORED DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO IMPROVE AKI OUTCOMES AND PREVENT KIDNEY DISEASE PROGRESSION. 2021 11 4016 24 LOW-DOSE HYDRALAZINE PREVENTS FIBROSIS IN A MURINE MODEL OF ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) AND PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD) ARE INTRINSICALLY TIED SYNDROMES. IN THIS REGARD, THE ACUTELY INJURED KIDNEY OFTEN DOES NOT ACHIEVE ITS FULL REGENERATIVE CAPACITY AND AKI DIRECTLY TRANSITIONS INTO PROGRESSIVE CKD ASSOCIATED WITH TUBULOINTERSTITIAL FIBROSIS. UNDERLYING MECHANISMS OF SUCH AKI-TO-CKD PROGRESSION ARE STILL INCOMPLETELY UNDERSTOOD AND SPECIFIC THERAPEUTIC INTERVENTIONS ARE STILL ELUSIVE. BECAUSE EPIGENETIC MODIFICATIONS PLAY A ROLE IN MAINTAINING TISSUE FIBROSIS, WE USED A MURINE MODEL OF ISCHEMIA-REPERFUSION INJURY TO DETERMINE WHETHER ABERRANT PROMOTER METHYLATION OF RASAL1 CONTRIBUTES CAUSALLY TO THE SWITCH BETWEEN PHYSIOLOGICAL REGENERATION AND TUBULOINTERSTITIAL FIBROGENESIS, A HALLMARK OF AKI-TO-CKD PROGRESSION. IT IS KNOWN THAT THE ANTIHYPERTENSIVE DRUG HYDRALAZINE HAS DEMETHYLATING ACTIVITY, AND THAT ITS OPTIMUM DEMETHYLATING ACTIVITY OCCURS AT CONCENTRATIONS BELOW BLOOD PRESSURE-LOWERING DOSES. ADMINISTRATION OF LOW-DOSE HYDRALAZINE EFFECTIVELY INDUCED EXPRESSION OF HYDROXYLASE TET3, WHICH CATALYZED RASAL1 HYDROXYMETHYLATION AND SUBSEQUENT RASAL1 PROMOTER DEMETHYLATION. HYDRALAZINE-INDUCED CPG PROMOTER DEMETHYLATION SUBSEQUENTLY ATTENUATED RENAL FIBROSIS AND PRESERVED EXCRETORY RENAL FUNCTION INDEPENDENT OF ITS BLOOD PRESSURE-LOWERING EFFECTS. IN COMPARISON, RASAL1 DEMETHYLATION AND INHIBITION OF TUBULOINTERSTITIAL FIBROSIS WAS NOT DETECTED UPON ADMINISTRATION OF THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR RAMIPRIL IN THIS MODEL. THUS, RASAL1 PROMOTER METHYLATION AND SUBSEQUENT TRANSCRIPTIONAL RASAL1 SUPPRESSION PLAYS A CAUSAL ROLE IN AKI-TO-CKD PROGRESSION. 2017 12 4381 38 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 13 3466 32 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 14 2537 26 EPIGENETICS IN HEART FAILURE PHENOTYPES. CHRONIC HEART FAILURE (HF) IS A LEADING CLINICAL AND PUBLIC PROBLEM POSING A HIGHER RISK OF MORBIDITY AND MORTALITY IN DIFFERENT POPULATIONS. HF APPEARS TO BE IN BOTH PHENOTYPIC FORMS: HF WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION (HFREF) AND HF WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION (HFPEF). ALTHOUGH BOTH HF PHENOTYPES CAN BE DISTINGUISHED THROUGH CLINICAL FEATURES, CO-MORBIDITY STATUS, PREDICTION SCORE, AND TREATMENT, THE CLINICAL OUTCOMES IN PATIENTS WITH HFREF AND HFPEF ARE SIMILAR. IN THIS CONTEXT, INVESTIGATION OF VARIOUS MOLECULAR AND CELLULAR MECHANISMS LEADING TO THE DEVELOPMENT AND PROGRESSION OF BOTH HF PHENOTYPES IS VERY IMPORTANT. THERE IS EMERGING EVIDENCE THAT EPIGENETIC REGULATION MAY HAVE A CLUE IN THE PATHOGENESIS OF HF. THIS REVIEW REPRESENTS CURRENT AVAILABLE EVIDENCE REGARDING THE IMPLICATION OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF DIFFERENT HF PHENOTYPES AND PERSPECTIVES OF EPIGENETIC-BASED THERAPIES OF HF. 2016 15 5068 31 PHYSICAL ACTIVITY AND PROGENITOR CELL-MEDIATED ENDOTHELIAL REPAIR IN CHRONIC HEART FAILURE: IS THERE A ROLE FOR EPIGENETICS? CHRONIC HEART FAILURE (CHF) IS THE MOST COMMON CARDIAC DISEASE AMONG THE ELDERLY AND A LEADING CAUSE OF MORTALITY IN ELDERLY PATIENTS. ENDOTHELIAL DYSFUNCTION IS HELD TO HAVE A MAJOR ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHF, WHICH RESULTS IN PROGRESSIVELY IMPAIRED FUNCTIONAL CAPACITY. ENDOTHELIAL PROGENITOR CELLS (EPCS) AND CIRCULATING ANGIOGENIC CELLS (CACS) ARE THE MAIN PLAYERS INVOLVED IN THE ENDOGENOUS REPAIR MECHANISMS THAT CAN COUNTERACT ENDOTHELIAL DYSFUNCTION. A MOUNTING BODY OF DATA INDICATES THAT EXERCISE ENHANCES ENDOTHELIAL RENEWAL THROUGH MOBILIZATION OF BONE MARROW-DERIVED EPCS AND CACS, MAKING IT AN EFFECTIVE THERAPEUTIC TOOL FOR CHF. INTERESTINGLY, EMERGING EVIDENCE HAS BEEN SHOWING THAT EXERCISE TRAINING CAN ALSO PROMOTE EPIGENETIC MODIFICATIONS, E.G. DNA METHYLATION, HISTONE MODIFICATIONS, AND DIFFERENTIAL EXPRESSION OF SPECIFIC NON-CODING RNAS LIKE MICRORNA (MIRNAS). SINCE DEREGULATION OF THE MIRNAS INVOLVED IN ENDOTHELIAL FUNCTION MODULATION HAS WIDELY BEEN DOCUMENTED IN CIRCULATING CELLS AND PLASMA OF CHF PATIENTS, DEREGULATION OF EPIGENETIC FEATURES COULD PLAY A KEY ROLE IN DISEASE PROGRESSION. HERE, WE REVIEW CURRENT KNOWLEDGE OF THE CONTRIBUTION OF EPCS AND CACS TO ENDOTHELIAL REPAIR MECHANISMS IN CHF PATIENTS, FOCUSING ON THE EFFECTS INDUCED BY EXERCISE TRAINING AND HYPOTHESIZING THAT SOME OF THESE EFFECTS CAN BE MEDIATED BY EPIGENETIC MECHANISMS. 2016 16 221 37 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 17 1074 22 CLONAL HAEMATOPOIESIS IN CHRONIC ISCHAEMIC HEART FAILURE: PROGNOSTIC ROLE OF CLONE SIZE FOR DNMT3A- AND TET2-DRIVER GENE MUTATIONS. AIMS: SOMATIC MUTATIONS OF THE EPIGENETIC REGULATORS DNMT3A AND TET2 CAUSING CLONAL EXPANSION OF HAEMATOPOIETIC CELLS (CLONAL HAEMATOPOIESIS; CH) WERE SHOWN TO BE ASSOCIATED WITH POOR PROGNOSIS IN CHRONIC ISCHAEMIC HEART FAILURE (CHF). THE AIM OF OUR ANALYSIS WAS TO DEFINE A THRESHOLD OF VARIANT ALLELE FREQUENCY (VAF) FOR THE PROGNOSTIC SIGNIFICANCE OF CH IN CHF. METHODS AND RESULTS: WE ANALYSED BONE MARROW AND PERIPHERAL BLOOD-DERIVED CELLS FROM 419 PATIENTS WITH CHF BY ERROR-CORRECTED AMPLICON SEQUENCING. CUT-OFF VAFS WERE OPTIMIZED BY MAXIMIZING SENSITIVITY PLUS SPECIFICITY FROM A TIME-DEPENDENT RECEIVER OPERATING CHARACTERISTIC (ROC) CURVE ANALYSIS FROM CENSORED DATA. 56.2% OF PATIENTS WERE CARRIERS OF A DNMT3A- (N = 173) OR A TET2- (N = 113) MUTATION WITH A VAF >0.5%, WITH 59 PATIENTS HARBOURING MUTATIONS IN BOTH GENES. SURVIVAL ROC ANALYSES REVEALED AN OPTIMIZED CUT-OFF VALUE OF 0.73% FOR TET2- AND 1.15% FOR DNMT3A-CH-DRIVER MUTATIONS. FIVE-YEAR-MORTALITY WAS 18% IN PATIENTS WITHOUT ANY DETECTED DNMT3A- OR TET2 MUTATION (VAF < 0.5%), 29% WITH ONLY ONE DNMT3A- OR TET2-CH-DRIVER MUTATIONS ABOVE THE RESPECTIVE CUT-OFF LEVEL AND 42% IN PATIENTS HARBOURING BOTH DNMT3A- AND TET2-CH-DRIVER MUTATIONS ABOVE THE RESPECTIVE CUT-OFF LEVELS. IN CARRIERS OF A DNMT3A MUTATION WITH VAF >/= 1.15%, 5-YEAR MORTALITY WAS 31%, COMPARED WITH 18% MORTALITY IN THOSE WITH VAF < 1.15% (P = 0.048). LIKEWISE, IN PATIENTS WITH TET2 MUTATIONS, 5-YEAR MORTALITY WAS 32% WITH VAF >/= 0.73%, COMPARED WITH 19% MORTALITY WITH VAF < 0.73% (P = 0.029). CONCLUSION: THE PRESENT STUDY DEFINES NOVEL THRESHOLD LEVELS FOR CLONE SIZE CAUSED BY ACQUIRED SOMATIC MUTATIONS IN THE CH-DRIVER GENES DNMT3A AND TET2 THAT ARE ASSOCIATED WITH WORSE OUTCOME IN PATIENTS WITH CHF. 2021 18 5370 22 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 19 2788 40 FACTORS AFFECTING THE TRANSITION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: POTENTIAL MECHANISMS AND FUTURE PERSPECTIVES. ACUTE KIDNEY INJURY (AKI) IS DEFINED AS A RAPID LOSS OF KIDNEY FUNCTION CHARACTERISED BY INFLAMMATION AND CELL DEATH, ULTIMATELY LEADING TO FURTHER FUNCTIONAL AND STRUCTURAL RENAL ALTERATIONS. BASED ON EXPERIMENTAL AND EPIDEMIOLOGICAL PIECES OF EVIDENCE, AKI MAY PROGRESS TO CHRONIC KIDNEY DISEASE (CKD) EVEN AFTER A RECOVERY PERIOD DUE TO MALADAPTIVE REPAIR AND OTHER UNDERLYING MECHANISMS SUCH AS HEIGHTENED WNT SIGNALLING, OVERSTIMULATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM (RAAS) PATHWAY, EPIGENETIC ALTERATIONS AND INHIBITION OF HYPOXIA-INDUCIBLE FACTOR (HIF) DEPENDENT DEFENCES. IT HAS BEEN REPORTED THAT RAAS ACTIVATION SUBSEQUENT TO RENAL INSULT MEDIATES INFLAMMATORY AND FIBROTIC MECHANISMS, WHICH ARE A HALLMARK OF CKD. MOREOVER, INTERESTING EVIDENCE REGARDING THE EXPOSURE-DEPENDENT DUAL ROLE OF WNT SIGNALLING IN BOTH INJURY AND REPAIR, EPIGENETIC CHANGES UNDERLYING KIDNEY DISEASE SUGGEST A POTENTIAL THERAPEUTIC ROLE OF THESE PATHWAYS IN AKI TO CKD CONTINUUM. IN ADDITION, THE HYPOXIA-INDEPENDENT RENAL BENEFITS OF ERYTHROPOIETIN SUCH AS ANTI-APOPTOSIS AND TUBULAR REGENERATION ALSO PRESENT AN AUSPICIOUS TARGET WHICH COULD BE USEFUL IN CLINICAL SETTINGS. IN THIS REVIEW, THE SPECIFIC ROLES OF THESE PATHWAYS IN KIDNEY DISEASE, THEIR PATHOLOGICAL MECHANISMS AND THERAPEUTIC STRATEGIES ARE DISCUSSED. MOREOVER, NOTABLE REPORTS CONCERNING STEM CELL THERAPY WHICH HOLD PROMISE IN HALTING AKI-CKD CONTINUUM WILL BE ELABORATED. 2019 20 6451 36 THERAPIES TARGETING EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. ACUTE KIDNEY INJURY (AKI) WAS PREVIOUSLY THOUGHT TO BE A MERELY TRANSIENT EVENT; HOWEVER, RECENT EPIDEMIOLOGICAL EVIDENCE SUPPORTS THE EXISTENCE OF A CAUSAL RELATIONSHIP BETWEEN AKI EPISODES AND SUBSEQUENT PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION IS NOT FULLY UNDERSTOOD, IT IS MEDIATED BY THE INTERPLAY AMONG MULTIPLE COMPONENTS OF THE KIDNEY INCLUDING TUBULAR EPITHELIAL CELLS, ENDOTHELIAL CELLS, PERICYTES, INFLAMMATORY CELLS, AND MYOFIBROBLASTS. EPIGENETIC ALTERATIONS INCLUDING HISTONE MODIFICATION, DNA METHYLATION, NON-CODING RNAS, AND CHROMATIN CONFORMATIONAL CHANGES, ARE ALSO EXPECTED TO BE LARGELY INVOLVED IN THE PATHOPHYSIOLOGY AS A "MEMORY" OF THE INITIAL INJURY THAT CAN PERSIST AND PREDISPOSE TO CHRONIC PROGRESSION OF FIBROSIS. EACH EPIGENETIC MODIFICATION HAS A GREAT POTENTIAL AS A THERAPEUTIC TARGET OF AKI-TO-CKD TRANSITION; TIMELY AND TARGET-SPECIFIC EPIGENETIC INTERVENTIONS TO THE VARIOUS TEMPORAL STAGES OF AKI-TO-CKD TRANSITION WILL BE THE KEY TO FUTURE THERAPEUTIC APPLICATIONS IN CLINICAL PRACTICE. THIS REVIEW ELABORATES ON THE LATEST KNOWLEDGE OF EACH MECHANISM AND THE CURRENTLY AVAILABLE THERAPEUTIC AGENTS THAT TARGET EPIGENETIC MODIFICATION IN THE CONTEXT OF AKI-TO-CKD TRANSITION. FURTHER STUDIES WILL ELUCIDATE MORE DETAILED MECHANISMS AND NOVEL THERAPEUTIC TARGETS OF AKI-TO-CKD TRANSITION. 2022