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 6810 38 [EPIGENETICS IN KIDNEY DISEASES]. INCREASING EVIDENCE HAS DEMONSTRATED THAT CHRONIC HYPOXIA IN THE TUBULOINTERSTITIUM RESULTS IN IRREVERSIBLE CHRONIC KIDNEY DISEASES. HYPOXIA INDUCIBLE FACTOR (HIF) IS A TRANSCRIPTIONAL MASTER REGULATOR WHICH TAKES CONTROL OF GENE EXPRESSIONS UNDER HYPOXIA. RECENTLY, HIF1 HAS BEEN REPORTED TO ORGANIZE A CLUSTER OF HISTONE-MODIFYING ENZYMES BY BINDING TO THEIR PROMOTER REGIONS IN VARIOUS KINDS OF CELL LINE. IN ORDER TO CLARIFY THE EPIGENETIC MOLECULAR MECHANISMS BY HIF1, WE EXAMINED THE GENOME-WIDE ANALYSIS OF HIF1-BINDING SITES (CHIP-SEQ) IN ENDOTHELIAL CELLS AND HIF1 DOWNSTREAM TARGET GENES USING DNA MICROARRAYS. CHIP-SEQ RESULTS DEMONSTRATED THAT HIF1 BINDS TO THE ENHANCER REGIONS IN ADDITION TO THE PROMOTER REGIONS. WE CLARIFIED THAT ONE OF THE HIF1 DOWNSTREAM GENES, SLC2A3 (SOLUTE-CARRIER FAMILY 2A3, ALSO KNOWN AS GLUCOSE TRANSPORTER 3: GLUT3), IS REGULATED BY CHANGING CHROMOSOMAL CONFORMATIONS UNDER HYPOXIA VIA A COOPERATIVE COMBINATION OF HIF1 AND KDM3A(LYSINE(K) SPECIFIC DEMETHYLASE 3A), ONE OF THE HISTONE DEMETHYLASES. KDM3A IS RECRUITED TO THE SLC2A3 LOCI IN AN HIF1-DEPENDENT MANNER AND DEMETHYLATES HISTONE REPRESSIVE MARK, H3K9ME2, UP-REGULATING ITS EXPRESSION. IN ADDITION, WE CONFIRMED THE INTERACTIONS OF HIF1 AND KDM3A ONLY UNDER HYPOXIA USING CO-IMMUNOPRECIPITATION. THESE EXPERIMENTAL RESULTS SHOWED NOVEL HIF1-DEPENDENT MOLECULAR MECHANISMS FROM AN EPIGENETIC VIEWPOINT. IT IS IMPORTANT TO ELUCIDATE THE EPIGENETIC MECHANISMS OF CHRONIC HYPOXIA IN ORDER TO IDENTIFY NOVEL THERAPEUTIC APPROACHES AGAINST CHRONIC KIDNEY DISEASE. 2014 5 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 6 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 7 2800 43 FEEDBACK REGULATORS OF HYPOXIA-INDUCIBLE FACTORS AND THEIR ROLE IN CANCER BIOLOGY. MALIGNANT TUMORS ARE CHARACTERIZED BY REGIONS OF LOW OXYGEN CONCENTRATION (HYPOXIA). THE HYPOXIC TUMOR MICROENVIRONMENT CONTRIBUTES TO TUMOR PROGRESSION BY ACTIVATING A SET OF ADAPTIVE RESPONSES VIA THE KEY TRANSCRIPTIONAL REGULATORS HIF-1ALPHA AND HIF-2ALPHA. THESE FACTORS HAVE BEEN TRADITIONALLY LINKED TO AN AGGRESSIVE TUMOR PHENOTYPE BY PROMOTING PROCESSES ESSENTIAL FOR TUMOR GROWTH, SUCH AS ANGIOGENESIS, GLYCOLYSIS, METASTASIS AND INVASION, AS WELL AS DIFFERENTIATION AND SELF RENEWAL. NOTABLY, THE COMPLEX HIF PATHWAY ALSO INITIATES ANTI-TUMORIGENIC MECHANISMS THAT LEAD TO CELL CYCLE ARREST OR CELL DEATH, INDICATING THE NEED FOR A STRINGENT CONTROL OF THE EXTENT AND THE DIRECTION OF THE HYPOXIA RESPONSE. THE IMPORTANCE OF THIS CONTROL FOR TUMOR CELL SURVIVAL IS ILLUSTRATED BY THE INTRICATE REGULATION OF HIF ACTIVITY AT THE MRNA, PROTEIN AND EPIGENETIC LEVEL BY A COMPLEX NETWORK OF POSITIVE AND NEGATIVE FEEDBACK REGULATORS. WE PROPOSE THAT THESE FEEDBACK REGULATORS HELP TO FLEXIBLY ADJUST AND ADAPT HIF ACTIVATED RESPONSES TO THE FLUCTUATING OXYGEN CONCENTRATIONS WITHIN TUMORS DURING ACUTE AND CHRONIC HYPOXIA AND TO CURTAIL THE TUMOR-SUPPRESSING COMPONENTS OF THE HIF PATHWAY. MOREOVER, FEEDBACK REGULATION OF HIF INDUCES A SWITCH FROM HIF-1ALPHA TO HIF-2ALPHA DRIVEN RESPONSES UNDER CHRONIC HYPOXIA WHICH MAY HAVE ESSENTIAL FUNCTIONS IN THE REGULATION OF TUMOR CELL DIFFERENTIATION AND TUMOR STEM CELL MAINTENANCE. GIVEN THEIR CENTRAL ROLE IN CANCER BIOLOGY, HIF FEEDBACK REGULATORS MAY REPRESENT AN ATTRACTIVE AND NOVEL ANTI-TUMOR THERAPY TARGET TO OVERCOME CELL DEATH RESISTANCE IN TUMORS. 2010 8 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 9 4746 39 NOVEL LNC RNA REGULATED BY HIF-1 INHIBITS APOPTOTIC CELL DEATH IN THE RENAL TUBULAR EPITHELIAL CELLS UNDER HYPOXIA. CHRONIC TUBULOINTERSTITIAL HYPOXIA PLAYS AN IMPORTANT ROLE AS THE FINAL COMMON PATHWAY TO END-STAGE RENAL DISEASE. HIF-1 (HYPOXIA-INDUCIBLE FACTOR-1) IS A MASTER TRANSCRIPTIONAL FACTOR UNDER HYPOXIA, REGULATING DOWNSTREAM TARGET GENES. GENOME-WIDE ANALYSIS OF HIF-1 BINDING SITES USING HIGH-THROUGHPUT SEQUENCERS HAS CLARIFIED VARIOUS KINDS OF DOWNSTREAM TARGETS AND MADE IT POSSIBLE TO DEMONSTRATE THE NOVEL ROLES OF HIF-1. OUR AIM OF THIS STUDY IS TO IDENTIFY NOVEL HIF-1 DOWNSTREAM EPIGENETIC TARGETS WHICH MAY PLAY IMPORTANT ROLES IN THE KIDNEY. IMMORTALIZED TUBULAR CELL LINES (HK2; HUMAN KIDNEY-2) AND PRIMARY CULTURED CELLS (RPTEC; RENAL PROXIMAL TUBULAR CELL LINES) WERE EXPOSED TO 1% HYPOXIA FOR 24-72 H. WE PERFORMED RNA-SEQ TO CLARIFY THE EXPRESSION OF MRNA AND LONG NON-CODING RNA (LNCRNA). WE ALSO EXAMINED CHIP-SEQ TO IDENTIFY HIF-1 BINDING SITES UNDER HYPOXIA. RNA-SEQ IDENTIFIED 44 LNCRNAS WHICH ARE UP-REGULATED UNDER HYPOXIC CONDITION IN BOTH CELLS. CHIP-SEQ ANALYSIS DEMONSTRATED THAT HIF-1 ALSO BINDS TO THE LNCRNAS UNDER HYPOXIA. THE EXPRESSION OF NOVEL LNCRNA, DARS-AS1 (ASPARTYL-TRNA SYNTHETASE ANTI-SENSE 1), IS UP-REGULATED ONLY UNDER HYPOXIA AND HIF-1 BINDS TO ITS PROMOTER REGION, WHICH INCLUDES TWO HYPOXIA-RESPONSIVE ELEMENTS. ITS EXPRESSION IS ALSO UP-REGULATED WITH COBALT CHLORIDE EXPOSURE, WHILE IT IS NOT UNDER HYPOXIA WHEN HIF-1 IS KNOCKED DOWN BY SIRNA TO CLARIFY THE BIOLOGICAL ROLES OF DARS-AS1, WE MEASURED THE ACTIVITY OF CASPASE 3/7 USING ANTI-SENSE OLIGO OF DARS-AS1. KNOCKDOWN OF DARS-AS1 DETERIORATED APOPTOTIC CELL DEATH. IN CONCLUSION, WE IDENTIFIED THE NOVEL LNCRNAS REGULATED BY HIF-1 UNDER HYPOXIA AND CLARIFIED THAT DARS-AS1 PLAYS AN IMPORTANT ROLE IN INHIBITING APOPTOTIC CELL DEATH IN RENAL TUBULAR CELLS. 2017 10 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 11 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 12 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 13 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 14 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 15 2023 26 EPIGENETIC CHANGES BY DNA METHYLATION IN CHRONIC AND INTERMITTENT HYPOXIA. DNA METHYLATION OF CYTOSINE RESIDUES IS A WELL-STUDIED EPIGENETIC CHANGE, WHICH REGULATES GENE TRANSCRIPTION BY ALTERING ACCESSIBILITY FOR TRANSCRIPTION FACTORS. HYPOXIA IS A PERVASIVE STIMULUS THAT AFFECTS MANY PHYSIOLOGICAL PROCESSES. THE CIRCULATORY AND RESPIRATORY SYSTEMS ADAPT TO CHRONIC SUSTAINED HYPOXIA, SUCH AS THAT ENCOUNTERED DURING A HIGH-ALTITUDE SOJOURN. MANY PEOPLE LIVING AT SEA LEVEL EXPERIENCE CHRONIC INTERMITTENT HYPOXIA (IH) DUE TO SLEEP APNEA, WHICH LEADS TO CARDIOVASCULAR AND RESPIRATORY MALADAPTATION. THIS ARTICLE PRESENTS A BRIEF UPDATE ON EMERGING EVIDENCE SUGGESTING THAT CHANGES IN DNA METHYLATION CONTRIBUTE TO PATHOLOGIES CAUSED BY CHRONIC IH AND POTENTIALLY MEDIATE ADAPTATIONS TO CHRONIC SUSTAINED HYPOXIA BY AFFECTING THE HYPOXIA-INDUCIBLE FACTOR (HIF) SIGNALING PATHWAY. 2017 16 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 17 6233 26 THE LONG NONCODING RNA TUG1 CONNECTS METABOLIC CHANGES WITH KIDNEY DISEASE IN PODOCYTES. AN INCREASING AMOUNT OF EVIDENCE SUGGESTS THAT METABOLIC ALTERATIONS PLAY A KEY ROLE IN CHRONIC KIDNEY DISEASE (CKD) PATHOGENESIS. IN THIS ISSUE OF THE JCI, LONG ET AL. REPORT THAT THE LONG NONCODING RNA (LNCRNA) TAURINE-UPREGULATED 1 (TUG1) CONTRIBUTES TO CKD DEVELOPMENT. THE AUTHORS SHOW THAT TUG1 REGULATES MITOCHONDRIAL FUNCTION IN PODOCYTES BY EPIGENETIC TARGETING OF EXPRESSION OF THE TRANSCRIPTION FACTOR PPARGAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA, ENCODED BY PPARGC1A). TRANSGENIC OVEREXPRESSION OF TUG1 SPECIFICALLY IN PODOCYTES AMELIORATED DIABETES-INDUCED CKD IN MICE. TOGETHER, THESE RESULTS HIGHLIGHT AN IMPORTANT CONNECTION BETWEEN LNCRNA-MEDIATED METABOLIC ALTERATIONS IN PODOCYTES AND KIDNEY DISEASE DEVELOPMENT. 2016 18 385 33 AN IMMORTALIZED CELL LINE DERIVED FROM RENAL ERYTHROPOIETIN-PRODUCING (REP) CELLS DEMONSTRATES THEIR POTENTIAL TO TRANSFORM INTO MYOFIBROBLASTS. THE ERYTHROID GROWTH FACTOR ERYTHROPOIETIN (EPO) IS PRODUCED BY RENAL INTERSTITIAL FIBROBLASTS, CALLED REP (RENAL EPO-PRODUCING) CELLS, IN A HYPOXIA-INDUCIBLE MANNER. IN CHRONIC KIDNEY DISEASE (CKD), REP CELLS LOSE THEIR EPO-PRODUCTION ABILITY, LEADING TO RENAL ANAEMIA. CONCURRENTLY, REP CELLS ARE SUGGESTED TO BE TRANSFORMED INTO MYOFIBROBLASTS, WHICH ARE THE MAJOR PLAYER OF RENAL FIBROSIS. ALTHOUGH ESTABLISHMENT OF CULTURED CELL LINES DERIVED FROM REP CELLS HAS BEEN A LONG-TERM CHALLENGE, WE HERE SUCCESSFULLY ESTABLISHED A REP-CELL-DERIVED IMMORTALIZED AND CULTIVABLE CELL LINE (REPLIC CELLS) BY USING A GENETICALLY MODIFIED MOUSE LINE. REPLIC CELLS EXHIBITED MYOFIBROBLASTIC PHENOTYPES AND LOST THEIR EPO-PRODUCTION ABILITY, REFLECTING THE SITUATION IN RENAL FIBROSIS. ADDITIONALLY, WE FOUND THAT CELL-AUTONOMOUS TGFBETA SIGNALLING CONTRIBUTES TO MAINTENANCE OF THE MYOFIBROBLASTIC FEATURES OF REPLIC CELLS. FURTHERMORE, THE PROMOTERS OF GENES FOR EPO AND HIF2ALPHA, A MAJOR ACTIVATOR OF EPO GENE EXPRESSION, WERE HIGHLY METHYLATED IN REPLIC CELLS. THUS, THESE RESULTS STRONGLY SUPPORT OUR CONTENTION THAT REP CELLS ARE THE ORIGIN OF MYOFIBROBLASTS IN FIBROTIC KIDNEYS AND DEMONSTRATE THAT CELL-AUTONOMOUS TGFBETA SIGNALLING AND EPIGENETIC SILENCING ARE INVOLVED IN RENAL FIBROSIS AND RENAL ANAEMIA, RESPECTIVELY, IN CKD. THE REPLIC CELL LINE IS A USEFUL TOOL TO FURTHER INVESTIGATE THE MOLECULAR MECHANISMS UNDERLYING RENAL FIBROSIS. 2019 19 4353 33 MIR-20B-5P ATTENUATES HYPOXIA-INDUCED APOPTOSIS IN CARDIOMYOCYTES VIA THE HIF-1ALPHA/NF-KAPPAB PATHWAY. CHRONIC HYPOXIA IS A COMMON INDUCER OF END-STAGE CARDIOVASCULAR DISEASE. IN CELLS UNDER HYPOXIA, THE HYPOXIA-INDUCIBLE FACTOR-1 (HIF-1) PLAYS A VITAL ROLE IN REGULATING DOWNSTREAM TARGET GENES. HOWEVER, THE MECHANISM OF HYPOXIA IN CARDIOMYOCYTES IS STILL UNCLEAR. IN THIS STUDY, WE AIMED TO IDENTIFY NOVEL DOWNSTREAM EPIGENETIC TARGETS OF HIF-1ALPHA IN CARDIOMYOCYTES UNDER HYPOXIA. H9C2 CELLS WERE EXPOSED TO HYPOXIA CONDITION, AND QUANTITATIVE REAL-TIME PCR ANALYSIS WAS PERFORMED TO EVALUATE THE EXPRESSION OF MIR-20B-5P. THE RESULTS INDICATED THAT THE EXPRESSION OF MIR-20B-5P WAS DOWN-REGULATED IN H9C2 CELLS UNDER LOW OXYGEN CONDITION. MEANWHILE, HIF-1ALPHA OVEREXPRESSION FURTHER DOWN-REGULATED THE MIR-20B-5P EXPRESSION IN H9C2 CELLS TRANSFECTED WITH HIF-1ALPHA PLASMIDS. IN ADDITION, ANNEXIN-V-FITC/PI FLOW CYTOMETRY ANALYSIS SUGGESTED THAT OVEREXPRESSION OF MIR-20B-5P ATTENUATED CELL APOPTOSIS UNDER HYPOXIA CONDITION IN H9C2 CELLS. WESTERN BLOT ANALYSIS SHOWED THAT THE HYPOXIA APPARENTLY INCREASED BAX AND CLEAVED-CASPASE-3, BUT DECREASED BCL-2 EXPRESSION IN H9C2 CELLS, INDICATING THAT HYPOXIA-INDUCED NF-KAPPAB SIGNALING PATHWAY ACTIVATION IS MEDIATED BY MIR-20B-5P. HYPOXIA-INDUCED H9C2 CELL APOPTOSIS WAS REDUCED AFTER HIF-1ALPHA KNOCKDOWN AS SHOWN BY THE FLOW CYTOMETRY ANALYSIS. IN CONCLUSION, WE IDENTIFIED THAT MIR-20B-5P PLAYS AN IMPORTANT ROLE IN MEDIATING CARDIOMYOCYTES APOPTOSIS UNDER HYPOXIA, WHICH IS MEDIATED BY THE HIF-1/NF-KAPPAB SIGNALING PATHWAY. 2020 20 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