1 5420 130 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 2 3467 34 HYPOXIA, HIF, AND ASSOCIATED SIGNALING NETWORKS IN CHRONIC KIDNEY DISEASE. THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD) IS COMPLEX AND APPARENTLY MULTIFACTORIAL. HYPOXIA OR DECREASE IN OXYGEN SUPPLY IN KIDNEY TISSUES HAS BEEN IMPLICATED IN CKD. HYPOXIA INDUCIBLE FACTORS (HIF) ARE A SMALL FAMILY OF TRANSCRIPTION FACTORS THAT ARE MAINLY RESPONSIVE TO HYPOXIA AND MEDIATE HYPOXIC RESPONSE. HIF PLAYS A CRITICAL ROLE IN RENAL FIBROSIS DURING CKD THROUGH THE MODULATION OF GENE TRANSCRIPTION, CROSSTALK WITH MULTIPLE SIGNALING PATHWAYS, EPITHELIAL-MESENCHYMAL TRANSITION, AND EPIGENETIC REGULATION. MOREOVER, HIF ALSO CONTRIBUTES TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL CONDITIONS ASSOCIATED WITH CKD, SUCH AS ANEMIA, INFLAMMATION, ABERRANT ANGIOGENESIS, AND VASCULAR CALCIFICATION. TREATMENTS TARGETING HIF AND RELATED SIGNALING PATHWAYS FOR CKD THERAPY ARE BEING DEVELOPED WITH PROMISING CLINICAL BENEFITS, ESPECIALLY FOR ANEMIA. THIS REVIEW PRESENTS AN UPDATED ANALYSIS OF HYPOXIA RESPONSE, HIF, AND THEIR ASSOCIATED SIGNALING NETWORK INVOLVED IN THE PATHOGENESIS OF CKD. 2017 3 5565 48 ROLE OF HYPOXIA IN PROGRESSIVE CHRONIC KIDNEY DISEASE AND IMPLICATIONS FOR THERAPY. PURPOSE OF REVIEW: CHRONIC HYPOXIA IN THE TUBULOINTERSTITIUM HAS BEEN RECOGNIZED AS A FINAL COMMON PATHWAY THAT LEADS TO THE DEVELOPMENT OF END-STAGE RENAL DISEASE. HYPOXIA-INDUCIBLE FACTOR (HIF), A MASTER REGULATOR OF THE ADAPTIVE RESPONSE AGAINST HYPOXIA, IS INVOLVED IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD). THIS REVIEW FOCUSES ON HIF AND NOVEL THERAPEUTIC STRATEGIES TARGETING HIF. RECENT FINDINGS: ALTHOUGH HIF UPREGULATION IS BENEFICIAL AGAINST HYPOXIC KIDNEY INJURY, IT MAY BE HARMFUL UNDER CERTAIN PATHOLOGICAL CONDITIONS. RECENT ADVANCES IN EPIGENETIC CHANGES PROVIDE AN ADDITIONAL LAYER OF COMPLEXITY TO OUR UNDERSTANDING OF GENE REGULATION IN RESPONSE TO HYPOXIA, WHICH IS MOST LIKELY INVOLVED IN THE PROGRESSION OF CKD. ON THE BASIS OF THIS NOVEL KNOWLEDGE, THE PHARMACOLOGICAL ACTIVATION AND MODULATION OF HIF IS EMERGING AS A NOVEL THERAPEUTIC TARGET. SUMMARY: HIF PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF CKD. THE UNDERLYING MOLECULAR MECHANISMS, INCLUDING EPIGENETICS, HAVE BEEN THOROUGHLY INVESTIGATED. ON THE BASIS OF THE EXPERIMENTAL DATA AVAILABLE TO DATE, THE PHARMACOLOGICAL ACTIVATION OF HIF IS LIKELY A NOVEL PROMISING THERAPY FOR CKD. 2014 4 4755 38 NOVEL THERAPEUTIC STRATEGY WITH HYPOXIA-INDUCIBLE FACTORS VIA REVERSIBLE EPIGENETIC REGULATION MECHANISMS IN PROGRESSIVE TUBULOINTERSTITIAL FIBROSIS. HYPOXIA-INDUCIBLE FACTOR (HIF) IS A TRANSCRIPTIONAL MASTER REGULATOR THAT TAKES CONTROL OF THE GENE EXPRESSIONS UNDER HYPOXIA. SEVERAL LINES OF EVIDENCE HAVE SHOWN THAT CHRONIC HYPOXIA IN TUBULOINTERSTITIUM RESULTS IN IRREVERSIBLE RENAL DISEASE. RECENTLY, HIF1 WAS REPORTED TO ORGANIZE A CLUSTER OF HISTONE-MODIFYING ENZYMES BY BINDING TO THEIR PROMOTER REGIONS IN VARIOUS KINDS OF CELL LINES. HOWEVER, ITS FUNCTION IN RENAL DISEASE REMAINS LARGELY UNKNOWN. WE FOCUSED ON THE EPIGENETIC REGULATION ON THE PROGRESSION OF CHRONIC KIDNEY DISEASE AND HAVE REVIEWED THE LATEST KNOWLEDGE IN THIS AREA WITH SPECIAL EMPHASIS ON THE INVOLVEMENT OF HIF. FOR EXAMPLE, A SET OF HIF1 DOWNSTREAM TARGET GENES ALSO WERE REPORTED TO BE REGULATED BY COOPERATIVE COMBINATION OF HIF1 AND HISTONE DEMETHYLASE. WE SUGGEST A NOVEL EPIGENETIC PATHWAY THAT AFFECTS THE FINAL COMMON PATHWAY TO END-STAGE RENAL DISEASE IN ADDITION TO THE TUBULOINTERSTITIAL HYPOXIA. WE EMPHASIZE THE IMPORTANCE OF FIGURING OUT THE EPIGENETIC MECHANISMS OF RENAL FAILURE TO FIND THE NOVEL THERAPEUTIC APPROACH OF CHRONIC KIDNEY DISEASE. 2013 5 3466 36 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 6 3338 26 HISTONE DEACETYLASE INHIBITORS: THE EPIGENETIC THERAPEUTICS THAT REPRESS HYPOXIA-INDUCIBLE FACTORS. HISTONE DEACETYLASE INHIBITORS (HDACIS) HAVE BEEN ACTIVELY EXPLORED AS A NEW GENERATION OF CHEMOTHERAPEUTICS FOR CANCERS, GENERALLY KNOWN AS EPIGENETIC THERAPEUTICS. RECENT FINDINGS INDICATE THAT SEVERAL TYPES OF HDACIS REPRESS ANGIOGENESIS, A PROCESS ESSENTIAL FOR TUMOR METABOLISM AND PROGRESSION. ACCUMULATING EVIDENCE SUPPORTS THAT THIS REPRESSION IS MEDIATED BY DISRUPTING THE FUNCTION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1, HIF-2, AND COLLECTIVELY, HIF), WHICH ARE THE MASTER REGULATORS OF ANGIOGENESIS AND CELLULAR ADAPTATION TO HYPOXIA. SINCE HIF ALSO REGULATE GLUCOSE METABOLISM, CELL SURVIVAL, MICROENVIRONMENT REMODELING, AND OTHER ALTERATIONS COMMONLY REQUIRED FOR TUMOR PROGRESSION, THEY ARE CONSIDERED AS NOVEL TARGETS FOR CANCER CHEMOTHERAPY. THOUGH THE PRECISE BIOCHEMICAL MECHANISM UNDERLYING THE HDACI-TRIGGERED REPRESSION OF HIF FUNCTION REMAINS UNCLEAR, POTENTIAL CELLULAR FACTORS THAT MAY LINK THE INHIBITION OF DEACETYLASE ACTIVITY TO THE REPRESSION OF HIF FUNCTION HAVE BEEN PROPOSED. HERE WE REVIEW PUBLISHED DATA THAT INHIBITORS OF TYPE I/II HDACS REPRESS HIF FUNCTION BY EITHER REDUCING FUNCTIONAL HIF-1ALPHA LEVELS, OR REPRESSING HIF-ALPHA TRANSACTIVATION ACTIVITY. IN ADDITION, UNDERLYING MECHANISMS AND POTENTIAL PROTEINS INVOLVED IN THE REPRESSION WILL BE DISCUSSED. A THOROUGH UNDERSTANDING OF HDACI-INDUCED REPRESSION OF HIF FUNCTION MAY FACILITATE THE DEVELOPMENT OF FUTURE THERAPIES TO EITHER REPRESS OR PROMOTE ANGIOGENESIS FOR CANCER OR CHRONIC ISCHEMIC DISORDERS, RESPECTIVELY. 2011 7 2034 34 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 8 2788 46 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 9 2614 38 EPIGENETICS: NEW QUESTIONS ON THE RESPONSE TO HYPOXIA. REDUCTION IN OXYGEN LEVELS BELOW NORMAL CONCENTRATIONS PLAYS IMPORTANT ROLES IN DIFFERENT NORMAL AND PATHOLOGICAL CONDITIONS, SUCH AS DEVELOPMENT, TUMORIGENESIS, CHRONIC KIDNEY DISEASE AND STROKE. ORGANISMS EXPOSED TO HYPOXIA TRIGGER CHANGES AT BOTH CELLULAR AND SYSTEMIC LEVELS TO RECOVER OXYGEN HOMEOSTASIS. MOST OF THESE PROCESSES ARE MEDIATED BY HYPOXIA INDUCIBLE FACTORS, HIFS, A FAMILY OF TRANSCRIPTION FACTORS THAT DIRECTLY INDUCE THE EXPRESSION OF SEVERAL HUNDRED GENES IN MAMMALIAN CELLS. ALTHOUGH DIFFERENT ASPECTS OF HIF REGULATION ARE WELL KNOWN, IT IS STILL UNCLEAR BY WHICH PRECISE MECHANISM HIFS ACTIVATE TRANSCRIPTION OF THEIR TARGET GENES. CONCOMITANTLY, HYPOXIA PROVOKES A DRAMATIC DECREASE OF GENERAL TRANSCRIPTION THAT SEEMS TO RELY IN PART ON EPIGENETIC CHANGES THROUGH A POORLY UNDERSTOOD MECHANISM. IN THIS REVIEW WE DISCUSS THE CURRENT KNOWLEDGE ON CHROMATIN CHANGES INVOLVED IN HIF DEPENDENT GENE ACTIVATION, AS WELL AS ON OTHER EPIGENETIC CHANGES, NOT NECESSARILY LINKED TO HIF THAT TAKE PLACE UNDER HYPOXIC CONDITIONS. 2011 10 6511 31 TRANSCRIPTION FACTORS AS THERAPEUTIC TARGETS IN CHRONIC KIDNEY DISEASE. THE GROWING NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS RECOGNIZED AS AN EMERGING PROBLEM WORLDWIDE. RECENT STUDIES HAVE INDICATED THAT DEREGULATION OF TRANSCRIPTION FACTORS IS ASSOCIATED WITH THE ONSET OR PROGRESSION OF KIDNEY DISEASE. SEVERAL CLINICAL TRIALS INDICATED THAT REGRESSION OF CKD MAY BE FEASIBLE VIA ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR ERYTHROID-2 RELATED FACTOR 2 (NRF2), WHICH SUGGESTS THAT TRANSCRIPTION FACTORS MAY BE POTENTIAL DRUG TARGETS FOR CKD. AGENTS STABILIZING HYPOXIA-INDUCIBLE FACTOR (HIF), WHICH MAY BE BENEFICIAL FOR RENAL ANEMIA AND RENAL PROTECTION, ARE ALSO NOW UNDER CLINICAL TRIAL. RECENTLY, WE HAVE REPORTED THAT THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4) REGULATES THE GLOMERULAR PODOCYTE EPIGENOME, AND THAT THE ANTIPROTEINURIC EFFECT OF THE RENIN(-)ANGIOTENSIN SYSTEM BLOCKADE MAY BE PARTIALLY MEDIATED BY KLF4. KLF4 IS ONE OF THE YAMANAKA FACTORS THAT INDUCES IPS CELLS AND IS REPORTED TO BE INVOLVED IN EPIGENETIC REMODELING. IN THIS ARTICLE, WE SUMMARIZE THE TRANSCRIPTION FACTORS ASSOCIATED WITH CKD AND PARTICULARLY FOCUS ON THE POSSIBILITY OF TRANSCRIPTION FACTORS BEING NOVEL DRUG TARGETS FOR CKD THROUGH EPIGENETIC MODULATION. 2018 11 221 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 12 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 13 4381 32 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 14 2293 36 EPIGENETIC REGULATION IN THE ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. EPIGENETIC MODIFICATIONS HAVE EMERGED AS A NEW, IMPORTANT CONTRIBUTOR TO GENE EXPRESSION REGULATION IN BOTH NORMAL AND PATHOPHYSIOLOGICAL CONDITIONS. EPIGENETICS HAVE BEEN STUDIED IN MANY DISEASES AND CONDITIONS SUCH AS ACUTE KIDNEY INJURY (AKI), A SYNDROME WITH A HIGH PREVALENCE THAT CARRIES A POOR PROGNOSIS WITH INCREASED MORBIDITY AND MORTALITY. IN ADDITION, IT HAS RECENTLY BEEN SHOWN THAT AKI INCREASES THE RISK FOR THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE SPECIFIC MOLECULAR MECHANISMS BY WHICH AKI INCREASES THE RISK OF CKD AND END STAGE RENAL DISEASE (ESRD) REMAIN UNKNOWN, ALTHOUGH THERE IS NEW EVIDENCE SUPPORTING A ROLE OF EPIGENETIC CHANGES. THE MOST STUDIED EPIGENETIC REGULATIONS IN AKI ARE CHROMATIN COMPACTION, DNA METHYLATION, AND HISTONE ACETYLATION/DEACETYLATION. THESE MODIFICATIONS PREDOMINANTLY INCREASE THE PRODUCTION OF PRO-INFLAMMATORY AND PROFIBROTIC CYTOKINES SUCH AS: MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), COMPLEMENT PROTEIN 3 (C3), TRANSFORMING GROWTH FACTOR BETA (TGF-BETA) THAT HAVE BEEN SHOWN FOR PERPETUATING INFLAMMATION, PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ULTIMATELY CAUSING RENAL FIBROSIS. A REVIEW OF EPIGENETIC MECHANISMS, THE PATHOPHYSIOLOGY OF AKI AND RECENT STUDIES THAT IMPLICATE EPIGENETIC MODIFICATIONS IN AKI AND IN THE TRANSITION TO CKD ARE DISCUSSED BELOW. 2015 15 4513 26 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 16 2193 36 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 17 6647 36 UPDATE OF PERICYTES FUNCTION AND THEIR ROLES IN KIDNEY DISEASES. STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT INVOLVEMENT OF KIDNEY PERICYTES IN RENAL FIBROSIS. KIDNEY PERICYTES, CLASSIFIED AS INTERSTITIAL MESENCHYMAL CELLS, ARE EXTENSIVELY BRANCHED, COLLAGEN-PRODUCING CELLS THAT CLOSELY INTERACT WITH ENDOTHELIAL CELLS. THIS ARTICLE AIMS TO PROVIDE AN OVERVIEW OF THE RECENT ADVANCEMENTS IN UNDERSTANDING THE PHYSIOLOGICAL FUNCTIONS OF PERICYTES AND THEIR ROLES IN KIDNEY DISEASES. IN A HEALTHY KIDNEY, PERICYTES HAVE ESSENTIAL PHYSIOLOGICAL FUNCTION IN ANGIOGENESIS, ERYTHROPOIETIN (EPO) PRODUCTION, AND THE REGULATION OF RENAL BLOOD FLOW. NEVERTHELESS, PERICYTE-MYOFIBROBLAST TRANSITION HAS BEEN IDENTIFIED AS THE PRIMARY CAUSE OF DISEASE PROGRESSION IN ACUTE KIDNEY INJURY (AKI)-TO-CHRONIC KIDNEY DISEASE (CKD) CONTINUUM. OUR RECENT RESEARCH HAS DEMONSTRATED THAT HYPOXIA-INDUCIBLE FACTOR-2ALPHA (HIF-2ALPHA) REGULATES ERYTHROPOIETIN PRODUCTION IN PERICYTES. HOWEVER, THIS PRODUCTION IS REPRESSED BY EPO GENE HYPERMETHYLATION AND HIF-2ALPHA DOWNREGULATION WHICH WERE INDUCED BY TRANSFORMING GROWTH FACTOR-BETA1-ACTIVATED DNA METHYLTRANSFERASE AND ACTIVIN RECEPTOR-LIKE KINASE-5 SIGNALING PATHWAY DURING RENAL FIBROSIS, RESPECTIVELY. ADDITIONALLY, AKI INDUCES EPIGENETIC MODIFICATIONS IN PERICYTES, RENDERING THEM MORE PRONE TO EXTRACELLULAR MATRIX PRODUCTION, CELL MIGRATION AND PROLIFERATION, THEREBY CONTRIBUTING TO SUBSEQUENT CAPILLARY RAREFACTION AND RENAL FIBROSIS. FURTHER INVESTIGATION INTO THE SPECIFIC FUNCTIONS AND ROLES OF DIFFERENT SUBPOPULATIONS OF PERICYTES MAY CONTRIBUTE FOR THE DEVELOPMENT OF TARGETED THERAPIES AIMED AT ATTENUATING KIDNEY DISEASE AND MITIGATING THEIR ADVERSE EFFECTS. 2023 18 6299 36 THE PROXIMAL TUBULE IS THE PRIMARY TARGET OF INJURY AND PROGRESSION OF KIDNEY DISEASE: ROLE OF THE GLOMERULOTUBULAR JUNCTION. THERE IS AN ALARMING GLOBAL INCREASE IN THE INCIDENCE OF END-STAGE KIDNEY DISEASE, FOR WHICH EARLY BIOMARKERS AND EFFECTIVE TREATMENT OPTIONS ARE LACKING. LARGELY BASED ON THE HISTOLOGY OF THE END-STAGE KIDNEY AND ON THE MODEL OF UNILATERAL URETERAL OBSTRUCTION, CURRENT INVESTIGATION IS FOCUSED ON THE PATHOGENESIS OF RENAL INTERSTITIAL FIBROSIS AS A CENTRAL MECHANISM IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). IT IS NOW RECOGNIZED THAT CUMULATIVE EPISODES OF ACUTE KIDNEY INJURY (AKI) CAN LEAD TO CKD, AND, CONVERSELY, CKD IS A RISK FACTOR FOR AKI. BASED ON RECENT AND HISTORIC STUDIES, THIS REVIEW SHIFTS ATTENTION FROM THE GLOMERULUS AND INTERSTITIUM TO THE PROXIMAL TUBULE AS THE PRIMARY SENSOR AND EFFECTOR IN THE PROGRESSION OF CKD AS WELL AS AKI. PACKED WITH MITOCHONDRIA AND DEPENDENT ON OXIDATIVE PHOSPHORYLATION, THE PROXIMAL TUBULE IS PARTICULARLY VULNERABLE TO INJURY (OBSTRUCTIVE, ISCHEMIC, HYPOXIC, OXIDATIVE, METABOLIC), RESULTING IN CELL DEATH AND ULTIMATELY IN THE FORMATION OF ATUBULAR GLOMERULI. ANIMAL MODELS OF HUMAN GLOMERULAR AND TUBULAR DISORDERS HAVE PROVIDED EVIDENCE FOR A BROAD REPERTOIRE OF MORPHOLOGICAL AND FUNCTIONAL RESPONSES OF THE PROXIMAL TUBULE, REVEALING PROCESSES OF DEGENERATION AND REPAIR THAT MAY LEAD TO NEW THERAPEUTIC STRATEGIES. MOST PROMISING ARE STUDIES THAT ENCOMPASS THE ENTIRE LIFE CYCLE FROM FETUS TO SENESCENCE, RECOGNIZING EPIGENETIC FACTORS. THE APPLICATION OF TECHNIQUES IN MOLECULAR CHARACTERIZATION OF TUBULE SEGMENTS AND THE DEVELOPMENT OF HUMAN KIDNEY ORGANOIDS MAY PROVIDE NEW INSIGHTS INTO THE MAMMALIAN KIDNEY SUBJECTED TO STRESS OR INJURY, LEADING TO BIOMARKERS OF EARLY CKD AND NEW THERAPIES. 2016 19 1474 38 DISTINCT PATTERNS OF TRANSCRIPTIONAL AND EPIGENETIC ALTERATIONS CHARACTERIZE ACUTE AND CHRONIC KIDNEY INJURY. ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD) ARE CONSIDERED EARLY AND LATE PHASES OF A PATHOLOGIC CONTINUUM OF INTERCONNECTED DISEASE STATES. ALTHOUGH CHANGES IN GENE EXPRESSION PATTERNS HAVE RECENTLY BEEN ELUCIDATED FOR THE TRANSITION OF AKI TO CKD, THE EPIGENETIC REGULATION OF KEY KIDNEY INJURY RELATED GENES REMAINS POORLY UNDERSTOOD. WE USED MULTIPLEX RT-QPCR, CHIP-QPCR AND INTEGRATIVE ANALYSIS TO COMPARE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT RENAL DISEASE-ASSOCIATED GENES ACROSS MOUSE AKI AND CKD MODELS. THESE STUDIES SHOWED THAT: (I) THERE ARE SUBSETS OF GENES WITH DISTINCT TRANSCRIPTIONAL AND EPIGENETICALLY PROFILES SHARED BY AKI AND CKD BUT ALSO SUBSETS THAT ARE SPECIFIC TO EITHER THE EARLY OR LATE STAGES OF RENAL INJURY; (II) DIFFERENCES IN EXPRESSION OF A SMALL NUMBER OF GENES IS SUFFICIENT TO DISTINGUISH AKI FROM CKD; (III) TRANSCRIPTION PLAYS A KEY ROLE IN THE UPREGULATION OF BOTH AKI AND CKD GENES WHILE POST-TRANSCRIPTIONAL REGULATION APPEARS TO PLAY A MORE SIGNIFICANT ROLE IN DECREASED EXPRESSION OF BOTH AKI AND CKD GENES; AND (IV) SUBSETS OF TRANSCRIPTIONALLY UPREGULATED GENES SHARE EPIGENETIC SIMILARITIES WHILE DOWNREGULATED GENES DO NOT. COLLECTIVELY, OUR STUDY SUGGESTS THAT IDENTIFIED COMMON TRANSCRIPTIONAL AND EPIGENETIC PROFILES OF KIDNEY INJURY LOCI COULD BE EXPLOITED FOR THERAPEUTIC TARGETING IN AKI AND CKD. 2018 20 6510 32 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS. 2015