1 6233 71 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 2 5571 29 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY. 2013 3 6363 25 THE ROLE OF LNCRNA TUG1 IN OBESITY-RELATED DISEASES. AS THE LIVING STANDARDS OF PEOPLE ARE INCREASINGLY IMPROVED, OBESITY HAS BECOME A HOTSPOT IN OUR DAILY LIFE. OBESITY HAS BEEN FOUND AS A CHRONIC AND RECURRENT DISEASE WITH SERIOUS ADVERSE CONSEQUENCES. OVER THE PAST FEW YEARS, SEVERAL ARTICLES INDICATED THAT LONG NON-CODING RNA TAURINE INCREASED GENE 1 (LNCRNA TUG1), A USEFUL RNA, WHICH WAS INDICATED TO SHOW A RELATIONSHIP TO OBESITY- RELATED DISEASE OCCURRENCE AND DEVELOPMENT. EXOSOMES ARE RECOGNIZED AS AN EMERGING RESEARCH FIELD THAT INCLUDES SUBSTANCES ACTIVELY INVOLVED IN REGULATING THE MOLECULAR MECHANISMS OF DISEASE. THIS REVIEW SUMMARIZES THE CURRENT RELEVANT TUG1 IN DIFFERENT MOLECULAR PATHWAYS OF OBESITYASSOCIATED DISEASES, THE CORRELATION BETWEEN EXOSOMES AND TUG1, OR OBESITY-ASSOCIATED DISEASES. THE AIM IS TO EXPLORE TUG1 AS A NOVEL TARGET FOR OBESITY, WHICH CAN DEEPEN THE KNOWLEDGE REGARDING THE EPIGENETIC REGULATION PATHWAY. FURTHERMORE, IT IS EXPECTED TO FOCUS ON DISEASES ASSOCIATED WITH OBESITY TREATMENT AND DIAGNOSIS. 2022 4 3957 23 LONG NON-CODING RNAS AS EMERGING REGULATORS OF MIRNAS AND EPIGENETICS IN DIABETES-RELATED CHRONIC KIDNEY DISEASE. DIABETES IS ONE OF THE MAJOR CAUSE OF CHRONIC KIDNEY DISEASE (CKD), INCLUDING "DIABETIC NEPHROPATHY," AND IS AN INCREASINGLY PREVALENT ACCELERATOR OF THE PROGRESSION OF NON-DIABETIC FORMS OF CKD. THE LONG NON-CODING RNAS (LNCRNAS) HAVE COME INTO THE LIMELIGHT IN THE PAST FEW YEARS AS ONE OF THE EMERGING WEAPONS AGAINST CKD IN DIABETES. AVAILABLE DATA OVER THE PAST FEW YEARS DEMONSTRATE THE INTERACTION OF LNCRNAS WITH MIRNAS AND EPIGENETIC MACHINERY. INTERESTINGLY, THE EVOLVING DATA SUGGEST THAT LNCRNAS PLAY A VITAL ROLE IN DIABETES-ASSOCIATED CKD BY REGULATION OF EPIGENETIC ENZYMES SUCH AS DNA METHYLTRANSFERASE, HISTONE DEACETYLASES, AND HISTONE METHYLTRANSFERASES. LNCRNAS ARE ALSO ENGAGED IN THE REGULATION OF SEVERAL MIRNAS IN DIABETIC NEPHROPATHY. HENCE THIS REVIEW WILL ELABORATE ON THE ASSOCIATION BETWEEN LNCRNAS AND THEIR INTERACTION WITH EPIGENETIC REGULATORS INVOLVED IN DIFFERENT ASPECTS AND THUS THE PROGRESSION OF CKD IN DIABETES. 2022 5 6510 22 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 6 2589 20 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 7 6511 20 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 4719 28 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 9 1983 27 EPIGENETIC ALTERATIONS IN PODOCYTES IN DIABETIC NEPHROPATHY. RECENTLY, EPIGENETIC ALTERATIONS HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF DIABETES AND ITS COMPLICATIONS. KIDNEY PODOCYTES, WHICH ARE GLOMERULAR EPITHELIAL CELLS, ARE IMPORTANT CELLS THAT FORM A SLIT MEMBRANE-A BARRIER FOR PROTEINURIA. PODOCYTES ARE TERMINALLY DIFFERENTIATED CELLS WITHOUT CELL DIVISION OR REPLENISHMENT ABILITIES. THEREFORE, PODOCYTE DAMAGE IS SUGGESTED TO BE ONE OF THE KEY FACTORS DETERMINING RENAL PROGNOSIS. RECENT STUDIES, INCLUDING OURS, SUGGEST THAT EPIGENETIC CHANGES IN PODOCYTES ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, THE ASSOCIATION BETWEEN DNA DAMAGE REPAIR AND EPIGENETIC CHANGES IN DIABETIC PODOCYTES HAS BEEN DEMONSTRATED. DETECTION OF PODOCYTE DNA DAMAGE AND EPIGENETIC CHANGES USING HUMAN SAMPLES, SUCH AS KIDNEY BIOPSY AND URINE-DERIVED CELLS, MAY BE A PROMISING STRATEGY FOR ESTIMATING KIDNEY DAMAGE AND RENAL PROGNOSES IN PATIENTS WITH DIABETES. TARGETING EPIGENETIC PODOCYTE CHANGES AND ASSOCIATED DNA DAMAGE MAY BECOME A NOVEL THERAPEUTIC STRATEGY FOR PREVENTING PROGRESSION TO END-STAGE RENAL DISEASE (ESRD) AND PROVIDE A POSSIBLE PROGNOSTIC MARKER IN DIABETIC NEPHROPATHY. THIS REVIEW SUMMARIZES RECENT ADVANCES REGARDING EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION, IN PODOCYTES IN DIABETIC NEPHROPATHY AND ADDRESSES DETECTION OF THESE ALTERATIONS IN HUMAN SAMPLES. ADDITIONALLY, WE FOCUSED ON DNA DAMAGE, WHICH IS INCREASED UNDER HIGH-GLUCOSE CONDITIONS AND ASSOCIATED WITH THE GENERATION OF EPIGENETIC CHANGES IN PODOCYTES. FURTHERMORE, EPIGENETIC MEMORY IN DIABETES IS DISCUSSED. UNDERSTANDING THE ROLE OF EPIGENETIC CHANGES IN PODOCYTES IN DIABETIC NEPHROPATHY MAY BE OF GREAT IMPORTANCE CONSIDERING THE INCREASING DIABETIC NEPHROPATHY PATIENT POPULATION IN AN AGING SOCIETY. 2021 10 1487 23 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 11 4992 24 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 12 2230 18 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 13 1866 19 EMERGING CROSSTALK BETWEEN LONG NON-CODING RNAS AND NRF2 SIGNALING. DIVERSE STIMULI TRIGGER NRF2 SIGNALING, WHICH IN TURN TRANSCRIPTIONALLY REGULATES AN ARRAY OF DOWNSTREAM TARGETS, PROVIDING FOR MULTIPLE LAYERS OF CONTROL. WHILE NRF2 ACTIVITY LARGELY IS GOVERNED BY POSTTRANSLATIONAL MODIFICATION OF CRITICAL THIOL RESIDUES IN THE PROTEIN PARTNER AND REDOX SENSOR KEAP1, FINE-TUNING IS PROVIDED BY ADDITIONAL MECHANISMS - INCLUDING EPIGENETIC REGULATION. HEREIN, WE REVIEW THE EMERGING SIGNIFICANCE OF LONG NON-CODING RNAS (LNCRNA) AS DOWNSTREAM TARGETS AND UPSTREAM REGULATORS OF THE NRF2 SIGNALING PATHWAY. AMONG THE ~16000 LNCRNAS IN GENCODE, SOME HAVE BEEN VALIDATED AS TRANSCRIPTIONALLY REGULATED BY NRF2 (E.G., LUCAT1, NMRAL2P, ODRUL, ROR AND TUG1), AND OTHERS HAVE BEEN IDENTIFIED AS UPSTREAM REGULATORS OF NRF2 EXPRESSION (E.G., HOTAIR, MALAT1, MEG1, NRAL AND UCA1). BIOINFORMATIC ANALYSES OF ANNOTATED HUMAN LNCRNAS IDENTIFIED PUTATIVE NRF2 BINDING SITES IN THE PROMOTER REGIONS OF 13,285 LNCRNAS. FURTHER INVESTIGATION IS WARRANTED TO VALIDATE THE MANY NOVEL LNCRNAS AS BONA FIDE NRF2-REGULATED TARGETS, AND THEIR ROLES IN NRF2 SIGNALING. NRF2 IS CONSIDERED A PROMISING THERAPEUTIC CANDIDATE FOR CANCER AND OTHER CHRONIC DISEASES; THUS, TARGETING THE ASSOCIATED LNCRNAS MIGHT PROVIDE FOR A MORE REFINED FINE-TUNING OF THE SYSTEM, DEPENDING ON CELLULAR AND PATHOPHYSIOLOGICAL CONTEXT. 2020 14 5923 27 TARGETING DNA METHYLATION IN PODOCYTES TO OVERCOME CHRONIC KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS ON THE RISE WORLDWIDE, AND THERE IS URGENT NEED FOR THE DEVELOPMENT OF EFFECTIVE PLANS AGAINST THE INCREASING INCIDENCE OF CKD. PODOCYTES, GLOMERULAR EPITHELIAL CELLS, ARE AN INTEGRAL PART OF THE PRIMARY FILTRATION UNIT OF THE KIDNEY AND FORM A SLIT MEMBRANE AS A BARRIER TO PREVENT PROTEINURIA. THE ROLE OF PODOCYTES IN THE PATHOGENESIS AND PROGRESSION OF CKD IS NOW RECOGNIZED. PODOCYTE FUNCTION DEPENDS ON A SPECIALIZED MORPHOLOGY WITH THE ARRANGED FOOT PROCESSES, WHICH IS DIRECTLY RELATED TO THEIR FUNCTION. EPIGENETIC CHANGES RESPONSIBLE FOR THE REGULATION OF GENE EXPRESSION RELATED TO PODOCYTE MORPHOLOGY HAVE BEEN SHOWN TO BE IMPORTANT IN THE PATHOGENESIS OF CKD. ALTHOUGH EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA-BASED REGULATION, WE HAVE FOCUSED ON DNA METHYLATION CHANGES BECAUSE THEY ARE MORE STABLE THAN OTHER EPIGENETIC MODIFICATIONS. THIS REVIEW SUMMARIZES RECENT LITERATURE ABOUT THE ROLE OF ALTERED DNA METHYLATION IN THE KIDNEY, ESPECIALLY IN GLOMERULAR PODOCYTES, FOCUSING ON TRANSCRIPTION FACTORS AND DNA DAMAGE RESPONSES THAT ARE CLOSELY ASSOCIATED WITH THE FORMATION OF DNA METHYLATION CHANGES. 2023 15 6075 27 THE DYNAMICS AND PLASTICITY OF EPIGENETICS IN DIABETIC KIDNEY DISEASE: THERAPEUTIC APPLICATIONS VIS-A-VIS. CHRONIC KIDNEY DISEASE (CKD) REFERS TO THE PHENOMENON OF PROGRESSIVE DECLINE IN THE GLOMERULAR FILTRATION RATE ACCOMPANIED BY ADVERSE CONSEQUENCES, INCLUDING FLUID RETENTION, ELECTROLYTE IMBALANCE, AND AN INCREASED CARDIOVASCULAR RISK COMPARED TO THOSE WITH NORMAL RENAL FUNCTION. THE TRIGGERS FOR THE IRREVERSIBLE RENAL FUNCTION DETERIORATION ARE MULTIFACTORIAL, AND DIABETES MELLITUS SERVES AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF CKD, NAMELY DIABETIC KIDNEY DISEASE (DKD). RECENTLY, EPIGENETIC DYSREGULATION EMERGED AS A PIVOTAL PLAYER STEERING THE PROGRESSION OF DKD, PARTLY RESULTING FROM HYPERGLYCEMIA-ASSOCIATED METABOLIC DISTURBANCES, RISING OXIDATIVE STRESS, AND/OR UNCONTROLLED INFLAMMATION. IN THIS REVIEW, WE DESCRIBE THE MAJOR EPIGENETIC MOLECULAR MECHANISMS, FOLLOWED BY SUMMARIZING CURRENT UNDERSTANDINGS OF THE EPIGENETIC ALTERATIONS PERTAINING TO DKD. WE HIGHLIGHT THE EPIGENETIC REGULATORY PROCESSES INVOLVED IN SEVERAL CRUCIAL RENAL CELL TYPES: MESANGIAL CELLS, PODOCYTES, TUBULAR EPITHELIA, AND GLOMERULAR ENDOTHELIAL CELLS. FINALLY, WE HIGHLIGHT EPIGENETIC BIOMARKERS AND RELATED THERAPEUTIC CANDIDATES THAT HOLD PROMISING POTENTIAL FOR THE EARLY DETECTION OF DKD AND THE AMELIORATION OF ITS PROGRESSION. 2022 16 6230 23 THE LONG NONCODING RNA LANDSCAPE IN HYPOXIC AND INFLAMMATORY RENAL EPITHELIAL INJURY. LONG NONCODING RNAS (LNCRNAS) ARE EMERGING AS KEY SPECIES-SPECIFIC REGULATORS OF CELLULAR AND DISEASE PROCESSES. TO IDENTIFY POTENTIAL LNCRNAS RELEVANT TO ACUTE AND CHRONIC RENAL EPITHELIAL INJURY, WE PERFORMED UNBIASED WHOLE TRANSCRIPTOME PROFILING OF HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS (PTECS) IN HYPOXIC AND INFLAMMATORY CONDITIONS. RNA SEQUENCING REVEALED THAT THE PROTEIN-CODING AND NONCODING TRANSCRIPTOMIC LANDSCAPE DIFFERED BETWEEN HYPOXIA-STIMULATED AND CYTOKINE-STIMULATED HUMAN PTECS. HYPOXIA- AND INFLAMMATION-MODULATED LNCRNAS WERE PRIORITIZED FOR FOCUSED FOLLOWUP ACCORDING TO THEIR DEGREE OF INDUCTION BY THESE STRESS STIMULI, THEIR EXPRESSION IN HUMAN KIDNEY TISSUE, AND WHETHER EXPOSURE OF HUMAN PTECS TO PLASMA OF CRITICALLY ILL SEPSIS PATIENTS WITH ACUTE KIDNEY INJURY MODULATED THEIR EXPRESSION. FOR THREE LNCRNAS (MIR210HG, LINC-ATP13A4-8, AND LINC-KIAA1737-2) THAT FULFILLED OUR CRITERIA, WE VALIDATED THEIR EXPRESSION PATTERNS, EXAMINED THEIR LOCI FOR CONSERVATION AND SYNTENY, AND DEFINED THEIR ASSOCIATED EPIGENETIC MARKS. THE LNCRNA LANDSCAPE CHARACTERIZED HERE PROVIDES INSIGHTS INTO NOVEL TRANSCRIPTOMIC VARIATIONS IN THE RENAL EPITHELIAL CELL RESPONSE TO HYPOXIC AND INFLAMMATORY STRESS. 2015 17 3403 22 HOW EPIGENETIC MODIFICATIONS DRIVE THE EXPRESSION AND MEDIATE THE ACTION OF PGC-1ALPHA IN THE REGULATION OF METABOLISM. EPIGENETIC CHANGES ARE A HALLMARK OF SHORT- AND LONG-TERM TRANSCRIPTIONAL REGULATION, AND HENCE INSTRUMENTAL IN THE CONTROL OF CELLULAR IDENTITY AND PLASTICITY. EPIGENETIC MECHANISMS LEADING TO CHANGES IN CHROMATIN STRUCTURE, ACCESSIBILITY FOR RECRUITMENT OF TRANSCRIPTIONAL COMPLEXES, AND INTERACTION OF ENHANCERS AND PROMOTERS ALL CONTRIBUTE TO ACUTE AND CHRONIC ADAPTATIONS OF CELLS, TISSUES AND ORGANS TO INTERNAL AND EXTERNAL PERTURBATIONS. SIMILARLY, THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA) IS ACTIVATED BY STIMULI THAT ALTER THE CELLULAR ENERGETIC DEMAND, AND SUBSEQUENTLY CONTROLS COMPLEX TRANSCRIPTIONAL NETWORKS RESPONSIBLE FOR CELLULAR PLASTICITY. IT THUS IS OF NO SURPRISE THAT PGC-1ALPHA IS UNDER THE CONTROL OF EPIGENETIC MECHANISMS, AND CONSTITUTES A MEDIATOR OF EPIGENETIC CHANGES IN VARIOUS TISSUES AND CONTEXTS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE LINK BETWEEN EPIGENETICS AND PGC-1ALPHA IN HEALTH AND DISEASE. 2019 18 3826 22 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 19 1515 24 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 20 2686 12 EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS IN THE PROGRESSION OF RENAL FIBROGENESIS. EPIGENETICS ARE OMNIPRESENT IN EUKARYOTIC CELLS AND INFLUENCE CELL DIFFERENTIATION AND MAINTENANCE OF CELL METABOLISM IN HEALTH AND DISEASE. HERE, WE DISCUSS HOW THE 'SECOND GENETIC CODE' IMPACTS THE FATE OF THE INJURED KIDNEY. WE PROVIDE A GLIMPSE OF HOW RECENT INSIGHTS INTO EPIGENETIC MECHANISMS OF CHRONIC KIDNEY DISEASE MIGHT LEAD TO NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS. 2014