1 4755 102 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 2 5565 40 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 3 6510 40 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 4 3467 27 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 5 4668 31 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 6 3338 35 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 6511 36 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 8 2589 28 EPIGENETICS OF PROGRESSION OF CHRONIC KIDNEY DISEASE: FACT OR FANTASY? EPIGENETIC MODIFICATIONS ARE IMPORTANT IN THE NORMAL FUNCTIONING OF THE CELL, FROM REGULATING DYNAMIC EXPRESSION OF ESSENTIAL GENES AND ASSOCIATED PROTEINS TO REPRESSING THOSE THAT ARE UNNEEDED. EPIGENETIC CHANGES ARE ESSENTIAL FOR DEVELOPMENT AND FUNCTIONING OF THE KIDNEY, AND ABERRANT METHYLATION, HISTONE MODIFICATIONS, AND EXPRESSION OF MICRORNA COULD LEAD TO CHRONIC KIDNEY DISEASE (CKD). HERE, EPIGENETIC MODIFICATIONS MODULATE TRANSFORMING GROWTH FACTOR BETA SIGNALING, INFLAMMATION, PROFIBROTIC GENES, AND THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, PROMOTING RENAL FIBROSIS AND PROGRESSION OF CKD. IDENTIFICATION OF THESE EPIGENETIC CHANGES IS IMPORTANT BECAUSE THEY ARE POTENTIALLY REVERSIBLE AND MAY SERVE AS THERAPEUTIC TARGETS IN THE FUTURE TO PREVENT SUBSEQUENT RENAL FIBROSIS AND CKD. IN THIS REVIEW WE DISCUSS THE DIFFERENT TYPES OF EPIGENETIC CONTROL, METHODS TO STUDY EPIGENETIC MODIFICATIONS, AND HOW EPIGENETICS PROMOTES PROGRESSION OF CKD. 2013 9 3826 33 INVESTIGATION OF EPIGENETICS IN KIDNEY CELL BIOLOGY. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN DNA OR ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN THE PROCESSES OF KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATIONS VIA EPIGENETIC REGULATORS AND INTERACTION VIA TRANSCRIPTION FACTORS, AND NONCODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, NEPHRITIC AND NEPHROTIC SYNDROMES, PYELONEPHRITIS AND POLYCYSTIC KIDNEY DISEASES ARE DRIVEN BY ABERRANT ACTIVITY IN NUMEROUS SIGNALING PATHWAYS IN EVEN INDIVIDUAL KIDNEY CELL. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, NONCODING RNAS, AND PROTEIN POSTTRANSLATIONAL MODIFICATIONS, COULD DISRUPT ESSENTIAL PATHWAYS THAT PROTECT THE RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND ESTABLISHMENT OF OTHER RENAL ASSOCIATED SYNDROMES, WHICH HAVE BEEN RECOGNIZED AS ONE OF THE CRITICAL MECHANISMS FOR REGULATING FUNCTIONAL CHANGES THAT DRIVE AND MAINTAIN THE KIDNEY DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE THE EPIGENETIC MECHANISMS IN KIDNEY CELL BIOLOGY AND EPIGENETIC BASIS OF KIDNEY DEVELOPMENT, AND INTRODUCE EPIGENETIC TECHNIQUES THAT CAN BE USED IN INVESTIGATING THE MOLECULAR MECHANISM OF KIDNEY CELL BIOLOGY AND KIDNEYS DISEASES, PRIMARILY FOCUSING ON THE INTEGRATION OF DNA METHYLATION AND CHROMATIN IMMUNOPRECIPITATION TECHNOLOGIES INTO KIDNEY DISEASE ASSOCIATED STUDIES. FUTURE STUDIES USING THESE EMERGING TECHNOLOGIES WILL ELUCIDATE HOW ALTERATIONS IN THE RENAL CELL EPIGENOME COOPERATE WITH GENETIC ABERRATIONS FOR KIDNEY DISEASE INITIATION AND PROGRESSION. INCORPORATING EPIGENOMIC TESTING INTO THE CLINICAL RESEARCH IS ESSENTIAL TO FUTURE STUDIES WITH EPIGENETICS BIOMARKERS AND PRECISION MEDICINE USING EMERGING EPIGENETIC THERAPIES. 2019 10 4250 37 METHYLATION-DEMETHYLATION DYNAMICS: IMPLICATIONS OF CHANGES IN ACUTE KIDNEY INJURY. OVER THE YEARS, THE EPIGENETIC LANDSCAPE HAS GROWN INCREASINGLY COMPLEX. UNTIL RECENTLY, METHYLATION OF DNA AND HISTONES WAS CONSIDERED ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS. HOWEVER, WITH THE DISCOVERY OF ENZYMES INVOLVED IN THE DEMETHYLATION PROCESS, SEVERAL EXCITING PROSPECTS HAVE EMERGED THAT FOCUS ON THE DYNAMIC REGULATION OF METHYLATION AND ITS CRUCIAL ROLE IN DEVELOPMENT AND DISEASE. AN INTERPLAY OF THE METHYLATION-DEMETHYLATION MACHINERY CONTROLS THE PROCESS OF GENE EXPRESSION. SINCE ACUTE KIDNEY INJURY (AKI), A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE AND DEATH, IS CHARACTERISED BY ABERRANT EXPRESSION OF GENES, UNDERSTANDING THE DYNAMICS OF METHYLATION AND DEMETHYLATION WILL PROVIDE NEW INSIGHTS INTO THE INTRICACIES OF THE DISEASE. RESEARCH ON EPIGENETICS IN AKI HAS ONLY MADE ITS MARK IN THE RECENT YEARS BUT HAS PROVIDED COMPELLING EVIDENCE THAT IMPLICATES THE INVOLVEMENT OF METHYLATION AND DEMETHYLATION CHANGES IN ITS PATHOPHYSIOLOGY. IN THIS REVIEW, WE EXPLORE THE ROLE OF METHYLATION AND DEMETHYLATION MACHINERY IN CELLULAR EPIGENETIC CONTROL AND FURTHER DISCUSS THE CONTRIBUTION OF METHYLOMIC CHANGES AND HISTONE MODIFICATIONS TO THE PATHOPHYSIOLOGY OF AKI. 2018 11 347 36 ALTERED DNA METHYLATION IN KIDNEY DISEASE: USEFUL MARKERS AND THERAPEUTIC TARGETS. RECENT STUDIES HAVE DEMONSTRATED THE ASSOCIATION OF ALTERED EPIGENOMES WITH LIFESTYLE-RELATED DISEASES. EPIGENETIC REGULATION PROMOTES BIOLOGICAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL CHANGES, AND SUCH PLASTICITY MAY CAUSE A 'MEMORY EFFECT', A SUSTAINED EFFECT OF TRANSIENT TREATMENT OR AN INSULT IN THE COURSE OF LIFESTYLE-RELATED DISEASES. WE INVESTIGATED THE SIGNIFICANCE OF EPIGENETIC CHANGES IN SEVERAL GENES REQUIRED FOR RENAL INTEGRITY, INCLUDING THE NEPHRIN GENE IN PODOCYTES, AND THE SUSTAINED ANTI-PROTEINURIC EFFECT, FOCUSING ON THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4). WE FURTHER REPORTED THE ROLE OF THE DNA REPAIR FACTOR LYSINE-ACETYL TRANSFERASE 5 (KAT5), WHICH ACTS COORDINATELY WITH KLF4, IN PODOCYTE INJURY CAUSED BY A HYPERGLYCEMIC STATE THROUGH THE ACCELERATION OF DNA DAMAGE AND EPIGENETIC ALTERATION. IN CONTRAST, KAT5 IN PROXIMAL TUBULAR CELLS PREVENTS ACUTE KIDNEY INJURY VIA GLOMERULAR FILTRATION REGULATION BY AN EPIGENETIC MECHANISM AS WELL AS PROMOTION OF DNA REPAIR, INDICATING THE CELL TYPE-SPECIFIC ACTION AND ROLES OF DNA REPAIR FACTORS. THIS REVIEW SUMMARIZES EPIGENETIC ALTERATIONS IN KIDNEY DISEASES, ESPECIALLY DNA METHYLATION, AND THEIR UTILITY AS MARKERS AND POTENTIAL THERAPEUTIC TARGETS. FOCUSING ON TRANSCRIPTION FACTORS OR DNA DAMAGE REPAIR FACTORS ASSOCIATED WITH EPIGENETIC CHANGES MAY BE MEANINGFUL DUE TO THEIR CELL-SPECIFIC EXPRESSION OR ACTION. WE BELIEVE THAT A BETTER UNDERSTANDING OF EPIGENETIC ALTERATIONS IN THE KIDNEY WILL LEAD TO THE DEVELOPMENT OF A NOVEL STRATEGY FOR CHRONIC KIDNEY DISEASE (CKD) TREATMENT. 2022 12 1487 34 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 13 2542 30 EPIGENETICS IN KIDNEY DISEASES. EPIGENETICS EXAMINES HERITABLE CHANGES IN DNA AND ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATION VIA EPIGENETIC REGULATORS AND NON-CODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS ARE MULTISTEP PROCESSES ASSOCIATED WITH NUMEROUS MOLECULAR ALTERATIONS EVEN IN INDIVIDUAL KIDNEY CELLS. EPIGENETIC ALTERATIONS, INCLUDING ANOMALOUS DNA METHYLATION, ABERRANT HISTONE ALTERATIONS AND CHANGES OF MICRORNA EXPRESSION ALL CONTRIBUTE TO KIDNEY PATHOGENESIS. THESE CHANGES ALTER THE GENOME-WIDE EPIGENETIC SIGNATURES AND DISRUPT ESSENTIAL PATHWAYS THAT PROTECT RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND DEVELOPMENT OF OTHER RENAL ASSOCIATED SYNDROMES. MOLECULAR CHANGES IMPACT CELLULAR FUNCTION WITHIN KIDNEY CELLS AND ITS MICROENVIRONMENT TO DRIVE AND MAINTAIN DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE EPIGENETIC MECHANISMS IN FOUR KIDNEY DISEASES INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS. WE PRIMARILY FOCUS ON CURRENT KNOWLEDGE ABOUT THE GENOME-WIDE PROFILING OF DNA METHYLATION AND HISTONE MODIFICATION, AND EPIGENETIC REGULATION ON SPECIFIC GENE(S) IN THE PATHOPHYSIOLOGY OF THESE DISEASES AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENT FOR PREVENTION AND THERAPY. INCORPORATING EPIGENOMIC TESTING INTO CLINICAL RESEARCH IS ESSENTIAL TO ELUCIDATE NOVEL EPIGENETIC BIOMARKERS AND DEVELOP PRECISION MEDICINE USING EMERGING THERAPIES. 2021 14 2230 32 EPIGENETIC MODIFICATIONS OF KLOTHO EXPRESSION IN KIDNEY DISEASES. DEVELOPMENTS OF MANY RENAL DISEASES ARE SUBSTANTIALLY INFLUENCED BY EPIGENETIC MODIFICATIONS OF NUMEROUS GENES, MAINLY MEDIATED BY DNA METHYLATIONS, HISTONE MODIFICATIONS, AND MICRORNA INTERFERENCE; HOWEVER, NOT ALL GENE MODIFICATIONS CAUSALLY AFFECT THE DISEASE ONSET OR PROGRESSION. KLOTHO IS A CRITICAL GENE WHOSE REPRESSIONS IN VARIOUS PATHOLOGICAL CONDITIONS REPORTEDLY INVOLVE EPIGENETIC REGULATORY MECHANISMS. KLOTHO IS ALMOST UNEXCEPTIONALLY REPRESSED EARLY AFTER ACUTE OR CHRONIC RENAL INJURIES AND ITS LEVELS INVERSELY CORRELATED WITH THE DISEASE PROGRESSION AND SEVERITY. MOREOVER, THE STRATEGIES OF KLOTHO DEREPRESSION VIA EPIGENETIC MODULATIONS BENEFICIALLY CHANGE THE PATHOLOGICAL COURSES BOTH IN VITRO AND IN VIVO. HENCE, KLOTHO IS NOT ONLY CONSIDERED A BIOMARKER OF THE RENAL DISEASE BUT ALSO A POTENTIAL OR EVEN AN IDEAL TARGET OF THERAPEUTIC EPIGENETIC INTERVENTION. HERE, WE SUMMARIZE AND DISCUSS STUDIES THAT INVESTIGATE THE KLOTHO REPRESSION AND INTERVENTION IN RENAL DISEASES FROM AN EPIGENETIC POINT OF VIEW. THESE INFORMATION MIGHT SHED NEW SIGHTS INTO THE EFFECTIVE THERAPEUTIC STRATEGIES TO PREVENT AND TREAT VARIOUS RENAL DISORDERS. 2021 15 3326 35 HISTONE DEACETYLASE 3 (HDAC3) AS AN IMPORTANT EPIGENETIC REGULATOR OF KIDNEY DISEASES. DEVELOPMENT AND PROGRESSION OF MANY KIDNEY DISEASES ARE SUBSTANTIALLY INFLUENCED BY ABERRANT PROTEIN ACETYLATION MODIFICATIONS OF GENE EXPRESSION CRUCIAL FOR KIDNEY FUNCTIONS. HISTONE DEACETYLASE (HDAC) EXPRESSION ALTERATIONS ARE DETECTED FROM RENAL SAMPLES OF PATIENTS AND ANIMAL MODELS OF VARIOUS KIDNEY DISEASES, AND THE ADMINISTRATIONS OF HDAC INHIBITORS DISPLAY IMPRESSIVE RENAL PROTECTIVE EFFECTS IN VITRO AND IN VIVO. HOWEVER, WHEN THE EXPRESSION ALTERATIONS OF MULTIPLE HDACS OCCUR, NOT ALL THE HDACS CAUSALLY AFFECT THE DISEASE ONSET OR PROGRESSION. IDENTIFICATION OF A SINGLE HDAC AS A DISEASE-CAUSING FACTOR WILL ALLOW SUBTYPE-TARGETED INTERVENTION WITH LESS SIDE EFFECT. HDAC3 IS A UNIQUE HDAC WITH DISTINCT STRUCTURAL AND SUBCELLULAR DISTRIBUTION FEATURES AND CO-REPRESSOR DEPENDENCY. HDAC3 IS REQUIRED FOR KIDNEY DEVELOPMENT AND ITS ABERRATIONS ACTIVELY PARTICIPATE IN MANY PATHOLOGICAL PROCESSES, SUCH AS CANCER, CARDIOVASCULAR DISEASES, DIABETES, AND NEURODEGENERATIVE DISORDERS, AND CONTRIBUTE SIGNIFICANTLY TO THE PATHOGENESIS OF KIDNEY DISEASES. THIS REVIEW WILL DISCUSS THE RECENT STUDIES THAT INVESTIGATE THE CRITICAL ROLES OF HDAC3 ABERRATIONS IN KIDNEY DEVELOPMENT, RENAL AGING, RENAL CELL CARCINOMA, RENAL FIBROSIS, CHRONIC KIDNEY DISEASE, POLYCYSTIC KIDNEY DISEASE, GLOMERULAR PODOCYTE INJURY, AND DIABETIC NEPHROPATHY. THESE STUDIES REVEAL THE DISTINCT CHARACTERS OF HDAC3 ABERRATIONS THAT ACT ON DIFFERENT MOLECULES/SIGNALING PATHWAYS UNDER VARIOUS RENAL PATHOLOGICAL CONDITIONS, WHICH MIGHT SHED LIGHTS INTO THE EPIGENETIC MECHANISMS OF RENAL DISEASES AND THE POTENTIALLY THERAPEUTIC STRATEGIES. 2022 16 4463 32 MOLECULAR MECHANISMS OF HISTONE DEACETYLASES AND INHIBITORS IN RENAL FIBROSIS PROGRESSION. RENAL FIBROSIS IS A COMMON PROGRESSIVE MANIFESTATION OF CHRONIC KIDNEY DISEASE. THIS PHENOMENON OF SELF-REPAIR IN RESPONSE TO KIDNEY DAMAGE SERIOUSLY AFFECTS THE NORMAL FILTRATION FUNCTION OF THE KIDNEY. YET, THERE ARE NO SPECIFIC TREATMENTS FOR THE CONDITION, WHICH MARKS FIBROSIS AS AN IRREVERSIBLE PATHOLOGICAL SEQUELA. AS SUCH, THERE IS A PRESSING NEED TO IMPROVE OUR UNDERSTANDING OF HOW FIBROSIS DEVELOPS AT THE CELLULAR AND MOLECULAR LEVELS AND EXPLORE SPECIFIC TARGETED THERAPIES FOR THESE PATHOGENIC MECHANISMS. IT IS NOW GENERALLY ACCEPTED THAT RENAL FIBROSIS IS A PATHOLOGICAL TRANSITION MEDIATED BY EXTRACELLULAR MATRIX (ECM) DEPOSITION, ABNORMAL ACTIVATION OF MYOFIBROBLASTS, AND EPITHELIAL-MESENCHYMAL TRANSITION (EMT) OF RENAL TUBULAR EPITHELIAL CELLS UNDER THE REGULATION OF TGF-BETA. HISTONE DEACETYLASES (HDACS) APPEAR TO PLAY AN ESSENTIAL ROLE IN PROMOTING RENAL FIBROSIS THROUGH NON-HISTONE EPIGENETIC MODIFICATIONS. IN THIS REVIEW, WE SUMMARIZE THE MECHANISMS OF RENAL FIBROSIS AND THE SIGNALING PATHWAYS THAT MIGHT BE INVOLVED IN HDACS IN RENAL FIBROSIS, AND THE SPECIFIC MECHANISMS OF ACTION OF VARIOUS HDAC INHIBITORS (HDACI) IN THE ANTI-FIBROTIC PROCESS TO ELUCIDATE HDACI AS A NOVEL THERAPEUTIC TOOL TO SLOW DOWN THE PROGRESSION OF RENAL FIBROSIS. 2022 17 2614 32 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 18 2195 32 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 19 1474 29 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 20 607 32 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011