1 6575 142 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 2 4137 46 MECHANISMS OF METABOLIC MEMORY AND RENAL HYPOXIA AS A THERAPEUTIC TARGET IN DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A WORLDWIDE PUBLIC HEALTH PROBLEM. THE DEFINITION OF DKD IS UNDER DISCUSSION. ALTHOUGH THE TERM DKD WAS ORIGINALLY DEFINED AS 'KIDNEY DISEASE SPECIFIC TO DIABETES,' DKD FREQUENTLY MEANS CHRONIC KIDNEY DISEASE WITH DIABETES MELLITUS AND INCLUDES NOT ONLY CLASSICAL DIABETIC NEPHROPATHY, BUT ALSO KIDNEY DYSFUNCTION AS A RESULT OF NEPHROSCLEROSIS AND OTHER CAUSES. METABOLIC MEMORY PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF VARIOUS COMPLICATIONS OF DIABETES, INCLUDING DKD. THE MECHANISMS OF METABOLIC MEMORY IN DKD ARE SUPPOSED TO INCLUDE ADVANCED GLYCATION END-PRODUCTS, DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RIBONUCLEIC ACID INCLUDING MICRO RIBONUCLEIC ACID. REGARDLESS OF THE PRESENCE OF DIABETES MELLITUS, THE FINAL COMMON PATHWAY IN CHRONIC KIDNEY DISEASE IS CHRONIC KIDNEY HYPOXIA, WHICH INFLUENCES EPIGENETIC PROCESSES, INCLUDING DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATION, AND CONFORMATIONAL CHANGES IN MICRO RIBONUCLEIC ACID AND CHROMATIN. THEREFORE, HYPOXIA AND OXIDATIVE STRESS ARE APPROPRIATE TARGETS OF THERAPIES AGAINST DKD. PROLYL HYDROXYLASE DOMAIN INHIBITOR ENHANCES THE DEFENSIVE MECHANISMS AGAINST HYPOXIA. BARDOXOLONE METHYL PROTECTS AGAINST OXIDATIVE STRESS, AND CAN EVEN REVERSE IMPAIRED RENAL FUNCTION; A PHASE 2 TRIAL WITH CONSIDERABLE ATTENTION TO HEART COMPLICATIONS IS CURRENTLY ONGOING IN JAPAN. 2017 3 4971 47 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 4 6648 52 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 5 2121 41 EPIGENETIC HISTONE MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD), AS THE MAIN COMPLICATION OF DIABETES MELLITUS, IS THE PRIMARY CAUSE OF THE END-STAGE RENAL DISEASE (ESRD) AND THE MOST COMMON CHRONIC KIDNEY DISEASE. OVERALL, 30-40% OF PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES EVENTUALLY DEVELOP DKD. ALTHOUGH SOME DIABETES PATIENTS HAVE INTENSIFIED GLYCEMIC CONTROL, THEY STILL DEVELOP DIABETIC KIDNEY DISEASE. CURRENT TREATMENT METHODS CAN ALLEVIATE BUT DO NOT MARKEDLY HALT DISEASE DEVELOPMENT, RESULTING IN RENAL FAILURE AND SEVERE COMPLICATIONS, EVEN CONTRIBUTING TO ELEVATED MORBIDITY AND MORTALITY RATES. DKD IS A DISEASE WITH INTERACTIONS OF GENES AND THE ENVIRONMENT. EMERGING EVIDENCE INDICATES THAT DKD-ASSOCIATED KEY GENES ARE ALSO REGULATED BY THE EPIGENETIC MECHANISM. RECENTLY, INCREASING RESEARCHES INVOLVING CELLS AND EXPERIMENTAL ANIMALS DEMONSTRATED THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS CAN MEDIATE GENE EXPRESSION, WHICH CORRELATED WITH DIABETIC KIDNEY DISEASE. NOVEL THERAPEUTIC STRATEGIES FOR EPIGENETIC EVENTS COULD BE BENEFICIAL FOR THE EARLY DETECTION AND TREATMENT OF DKD TO PREVENT IT FROM DEVELOPING INTO END-STAGE RENAL DISEASE (ESRD). IN THIS REVIEW, WE DISCUSS PRIOR FINDINGS IN THE FIELD OF HISTONE MODIFICATIONS IN DKD, ESPECIALLY HISTONE ACETYLATION AND HISTONE METHYLATION. WE THEN FOCUS ON RECENT DEVELOPMENTS IN HISTONE ACETYLATION AND METHYLATION INVOLVED IN THE PATHOGENESIS OF DKD. 2021 6 1832 40 EFFECTS OF METABOLIC MEMORY ON INFLAMMATION AND FIBROSIS ASSOCIATED WITH DIABETIC KIDNEY DISEASE: AN EPIGENETIC PERSPECTIVE. DIABETIC KIDNEY DISEASE (DKD) IS ONE OF THE MOST COMMON MICROVASCULAR COMPLICATION OF BOTH TYPE 1 (T1DM) AND TYPE 2 DIABETES MELLITUS (T2DM), AND THE LEADING CAUSE OF END-STAGE RENAL DISEASE (ESRD) WORLDWIDE. PERSISTENT INFLAMMATION AND SUBSEQUENT CHRONIC FIBROSIS ARE MAJOR CAUSES OF LOSS OF RENAL FUNCTION, WHICH IS ASSOCIATED WITH THE PROGRESSION OF DKD TO ESRD. IN FACT, DKD PROGRESSION IS AFFECTED BY A COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS. APPROXIMATELY, ONE-THIRD OF DIABETIC PATIENTS PROGRESS TO DEVELOP DKD DESPITE INTENSIVE GLYCEMIC CONTROL, WHICH PROPOSE AN ESSENTIAL CONCEPT "METABOLIC MEMORY." EPIGENETIC MODIFICATIONS, AN EXTENSIVELY STUDIED MECHANISM OF METABOLIC MEMORY, HAVE BEEN SHOWN TO CONTRIBUTE TO THE SUSCEPTIBILITY TO DEVELOP DKD. EPIGENETIC MODIFICATIONS ALSO PLAY A REGULATORY ROLE IN THE INTERACTIONS BETWEEN THE GENES AND THE ENVIRONMENTAL FACTORS. THE EPIGENETIC CONTRIBUTIONS TO THE PROCESSES OF INFLAMMATION AND FIBROGENESIS INVOLVED IN DKD OCCUR AT DIFFERENT REGULATORY LEVELS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNA MODULATION. COMPARED WITH GENETIC FACTORS, EPIGENETICS REPRESENTS A NEW THERAPEUTIC FRONTIER IN UNDERSTANDING THE DEVELOPMENT DKD AND MAY LEAD TO THERAPEUTIC BREAKTHROUGHS DUE TO THE POSSIBILITY TO REVERSE THESE MODIFICATIONS THERAPEUTICALLY. EARLY RECOGNITION OF EPIGENETIC EVENTS AND BIOMARKERS IS CRUCIAL FOR TIMELY DIAGNOSIS AND INTERVENTION OF DKD, AND FOR THE PREVENTION OF THE PROGRESSION OF DKD TO ESRD. HEREIN, WE WILL REVIEW THE LATEST EPIGENETIC MECHANISMS INVOLVED IN THE RENAL PATHOLOGY OF BOTH TYPE 1 (T1DN) AND TYPE 2 DIABETIC NEPHROPATHY (T2DN) AND HIGHLIGHT THE EMERGING ROLE AND POSSIBLE THERAPEUTIC STRATEGIES BASED ON THE UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DKD-ASSOCIATED INFLAMMATION AND FIBROGENESIS. 2021 7 5363 29 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 8 6075 30 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 9 2972 35 GENETIC AND EPIGENETIC STUDIES IN DIABETIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE IS A WORLDWIDE HEALTH CRISIS, WHILE DIABETIC KIDNEY DISEASE (DKD) HAS BECOME THE LEADING CAUSE OF END-STAGE RENAL DISEASE (ESRD). DKD IS A MICROVASCULAR COMPLICATION AND OCCURS IN 30-40% OF DIABETES PATIENTS. EPIDEMIOLOGICAL INVESTIGATIONS AND CLINICAL OBSERVATIONS ON THE FAMILIAL CLUSTERING AND HERITABILITY IN DKD HAVE HIGHLIGHTED AN UNDERLYING GENETIC SUSCEPTIBILITY. FURTHERMORE, DKD IS A PROGRESSIVE AND LONG-TERM DIABETIC COMPLICATION, IN WHICH EPIGENETIC EFFECTS AND ENVIRONMENTAL FACTORS INTERACT WITH AN INDIVIDUAL'S GENETIC BACKGROUND. IN RECENT YEARS, RESEARCHERS HAVE UNDERTAKEN GENETIC AND EPIGENETIC STUDIES OF DKD IN ORDER TO BETTER UNDERSTAND ITS MOLECULAR MECHANISMS. IN THIS REVIEW, CLINICAL MATERIAL, RESEARCH APPROACHES AND EXPERIMENTAL DESIGNS THAT HAVE BEEN USED FOR GENETIC AND EPIGENETIC STUDIES OF DKD ARE DESCRIBED. CURRENT INFORMATION FROM GENETIC AND EPIGENETIC STUDIES OF DKD AND ESRD IN PATIENTS WITH DIABETES, INCLUDING THE APPROACHES OF GENOME-WIDE ASSOCIATION STUDY (GWAS) OR EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) AND CANDIDATE GENE ASSOCIATION ANALYSES, ARE SUMMARIZED. FURTHER INVESTIGATION OF MOLECULAR DEFECTS IN DKD WITH NEW APPROACHES SUCH AS NEXT GENERATION SEQUENCING ANALYSIS AND PHENOME-WIDE ASSOCIATION STUDY (PHEWAS) IS ALSO DISCUSSED. 2019 10 1983 40 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 11 5300 40 PROTEIN METHYLATION IN DIABETIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY PERSISTENT URINE ABERRATIONS, STRUCTURAL ABNORMALITIES, OR IMPAIRED EXCRETORY RENAL FUNCTION. DIABETES IS THE LEADING CAUSE OF CKD. THEIR COMMON PATHOLOGICAL MANIFESTATION IS RENAL FIBROSIS. APPROXIMATELY HALF OF ALL PATIENTS WITH TYPE 2 DIABETES AND ONE-THIRD WITH TYPE 1 DIABETES WILL DEVELOP CKD. HOWEVER, RENAL FIBROSIS MECHANISMS ARE STILL POORLY UNDERSTOOD, ESPECIALLY POST-TRANSCRIPTIONAL AND EPIGENETIC REGULATION. AND AN UNMET NEED REMAINS FOR INNOVATIVE TREATMENT STRATEGIES FOR PREVENTING, ARRESTING, TREATING, AND REVERSING DIABETIC KIDNEY DISEASE (DKD). PEOPLE BELIEVE THAT PROTEIN METHYLATION, INCLUDING HISTONE AND NON-HISTONE, IS AN ESSENTIAL TYPE OF POST-TRANSLATIONAL MODIFICATION (PTM). HOWEVER, PREVALENT REVIEWS MAINLY FOCUS ON THE CAUSES SUCH AS DNA METHYLATION. THIS REVIEW WILL TAKE INSIGHTS INTO THE PROTEIN PART. FURTHERMORE, BY EMPHASIZING THE CLOSE RELATIONSHIP BETWEEN PROTEIN METHYLATION AND DKD, WE WILL SUMMARIZE THE CLINICAL RESEARCH STATUS AND FORESEE THE APPLICATION PROSPECT OF PROTEIN METHYLTRANSFERASE (PMT) INHIBITORS IN DKD TREATMENT. IN A NUTSHELL, OUR REVIEW WILL CONTRIBUTE TO A MORE PROFOUND UNDERSTANDING OF DKD'S MOLECULAR MECHANISM AND INSPIRE PEOPLE TO DIG INTO THIS FIELD. 2022 12 2236 33 EPIGENETIC MODIFIERS AS POTENTIAL THERAPEUTIC TARGETS IN DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE IS ONE OF THE FASTEST GROWING CAUSES OF DEATH WORLDWIDE. EPIGENETIC REGULATORS CONTROL GENE EXPRESSION AND ARE POTENTIAL THERAPEUTIC TARGETS. THERE IS FUNCTIONAL INTERVENTIONAL EVIDENCE FOR A ROLE OF DNA METHYLATION AND THE HISTONE POST-TRANSLATIONAL MODIFICATIONS-HISTONE METHYLATION, ACETYLATION AND CROTONYLATION-IN THE PATHOGENESIS OF KIDNEY DISEASE, INCLUDING DIABETIC KIDNEY DISEASE. READERS OF EPIGENETIC MARKS, SUCH AS BROMODOMAIN AND EXTRA TERMINAL (BET) PROTEINS, ARE ALSO THERAPEUTIC TARGETS. THUS, THE BD2 SELECTIVE BET INHIBITOR APABETALONE WAS THE FIRST EPIGENETIC REGULATOR TO UNDERGO PHASE-3 CLINICAL TRIALS IN DIABETIC KIDNEY DISEASE WITH AN ENDPOINT OF KIDNEY FUNCTION. THE DIRECT THERAPEUTIC MODULATION OF EPIGENETIC FEATURES IS POSSIBLE THROUGH PHARMACOLOGICAL MODULATORS OF THE SPECIFIC ENZYMES INVOLVED AND THROUGH THE THERAPEUTIC USE OF THE REQUIRED SUBSTRATES. OF FURTHER INTEREST IS THE CHARACTERIZATION OF POTENTIAL INDIRECT EFFECTS OF NEPHROPROTECTIVE DRUGS ON EPIGENETIC REGULATION. THUS, SGLT2 INHIBITORS INCREASE THE CIRCULATING AND TISSUE LEVELS OF BETA-HYDROXYBUTYRATE, A MOLECULE THAT GENERATES A SPECIFIC HISTONE MODIFICATION, BETA-HYDROXYBUTYRYLATION, WHICH HAS BEEN ASSOCIATED WITH THE BENEFICIAL HEALTH EFFECTS OF FASTING. TO WHAT EXTENT THIS IMPACT ON EPIGENETIC REGULATION MAY UNDERLIE OR CONTRIBUTE TO THE SO-FAR UNCLEAR MOLECULAR MECHANISMS OF CARDIO- AND NEPHROPROTECTION OFFERED BY SGLT2 INHIBITORS MERITS FURTHER IN-DEPTH STUDIES. 2020 13 2579 25 EPIGENETICS OF KIDNEY DISEASE. DNA METHYLATION AND HISTONE MODIFICATIONS DETERMINE RENAL PROGRAMMING AND THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. THE IDENTIFICATION OF THE WAY IN WHICH THE RENAL CELL EPIGENOME IS ALTERED BY ENVIRONMENTAL MODIFIERS DRIVING THE ONSET AND PROGRESSION OF RENAL DISEASES HAS EXTENDED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF KIDNEY DISEASE PROGRESSION. IN THIS REVIEW, WE FOCUS ON CURRENT KNOWLEDGE CONCERNING THE IMPLICATIONS OF EPIGENETIC MODIFICATIONS DURING RENAL DISEASE FROM EARLY DEVELOPMENT TO CHRONIC KIDNEY DISEASE PROGRESSION INCLUDING RENAL FIBROSIS, DIABETIC NEPHROPATHY AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENTS FOR THE PREVENTION AND THERAPY OF CHRONIC KIDNEY DISEASE AND END-STAGE KIDNEY DISEASE. 2017 14 6511 34 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 1515 37 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 16 3156 35 GLYCEMIC MEMORIES AND THE EPIGENETIC COMPONENT OF DIABETIC NEPHROPATHY. A STRONG CASE FOR THE DEREGULATION OF EPIGENETIC CHROMATIN MODIFICATIONS IN THE DEVELOPMENT AND PROGRESSION OF VARIOUS CHRONIC COMPLICATIONS OF DIABETES HAS EMERGED FROM RECENT EXPERIMENTAL OBSERVATIONS. CLINICAL TRIALS OF TYPE 1 AND TYPE 2 DIABETES PATIENTS HIGHLIGHT THE IMPORTANCE OF EARLY AND INTENSIVE TREATMENT AND THE PROLONGED DAMAGE OF HYPERGLYCEMIA ON ORGANS SUCH AS THE KIDNEY. THE FUNCTIONAL RELATIONSHIP BETWEEN THE REGULATION OF CHROMATIN ARCHITECTURE AND PERSISTENT GENE EXPRESSION CHANGES CONFERRED BY PRIOR HYPERGLYCEMIA REPRESENTS AN IMPORTANT AVENUE OF INVESTIGATION FOR EXPLAINING DIABETIC NEPHROPATHY. WHILE SEVERAL STUDIES IMPLICATE EPIGENETIC CHANGES AT THE CHROMATIN TEMPLATE IN THE DEREGULATED GENE EXPRESSION ASSOCIATED WITH DIABETIC NEPHROPATHY, THE MOLECULAR DETERMINANTS OF METABOLIC MEMORY IN RENAL CELLS REMAIN POORLY UNDERSTOOD. THERE IS NOW STRONG EVIDENCE FROM EXPERIMENTAL ANIMALS AND CELL CULTURE OF PERSISTENT GLUCOSE-DRIVEN CHANGES IN VASCULAR ENDOTHELIAL GENE EXPRESSION THAT MAY ALSO HAVE RELEVANCE FOR THE MICROVASCULATURE OF THE KIDNEY. EXPLORATION OF EPIGENETIC MECHANISMS UNDERLYING THE HYPERGLYCEMIC CUE MEDIATING PERSISTENT TRANSCRIPTIONAL CHANGES IN RENAL CELLS HOLDS NOVEL THERAPEUTIC POTENTIAL FOR DIABETIC NEPHROPATHY. 2013 17 6409 33 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019 18 6510 28 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 19 125 35 A SYSTEMS BIOLOGY OVERVIEW ON HUMAN DIABETIC NEPHROPATHY: FROM GENETIC SUSCEPTIBILITY TO POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL MODIFICATIONS. DIABETIC NEPHROPATHY (DN), A MICROVASCULAR COMPLICATION OCCURRING IN APPROXIMATELY 20-40% OF PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2DM), IS CHARACTERIZED BY THE PROGRESSIVE IMPAIRMENT OF GLOMERULAR FILTRATION AND THE DEVELOPMENT OF KIMMELSTIEL-WILSON LESIONS LEADING TO END-STAGE RENAL FAILURE (ESRD). THE CAUSES AND MOLECULAR MECHANISMS MEDIATING THE ONSET OF T2DM CHRONIC COMPLICATIONS ARE YET SKETCHY AND IT IS NOT CLEAR WHY DISEASE PROGRESSION OCCURS ONLY IN SOME PATIENTS. WE PERFORMED A SYSTEMATIC ANALYSIS OF THE MOST RELEVANT STUDIES INVESTIGATING GENETIC SUSCEPTIBILITY AND SPECIFIC TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND METABOLOMIC PATTERNS IN ORDER TO SUMMARIZE THE MOST SIGNIFICANT TRAITS ASSOCIATED WITH THE DISEASE ONSET AND PROGRESSION. THE PICTURE THAT EMERGES IS COMPLEX AND FASCINATING AS IT INCLUDES THE REGULATION/DYSREGULATION OF NUMEROUS BIOLOGICAL PROCESSES, CONVERGING TOWARD THE ACTIVATION OF INFLAMMATORY PROCESSES, OXIDATIVE STRESS, REMODELING OF CELLULAR FUNCTION AND MORPHOLOGY, AND DISTURBANCE OF METABOLIC PATHWAYS. THE GROWING INTEREST IN THE CHARACTERIZATION OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND THE IMPORTANCE OF HANDLING LARGE DATASETS USING A SYSTEMS BIOLOGY APPROACH ARE ALSO DISCUSSED. 2016 20 2795 39 FATTY LIVER AND CHRONIC KIDNEY DISEASE: NOVEL MECHANISTIC INSIGHTS AND THERAPEUTIC OPPORTUNITIES. CHRONIC KIDNEY DISEASE (CKD) IS A RISK FACTOR FOR END-STAGE RENAL DISEASE (ESRD) AND CARDIOVASCULAR DISEASE (CVD). ESRD OR CVD DEVELOP IN A SUBSTANTIAL PROPORTION OF PATIENTS WITH CKD RECEIVING STANDARD-OF-CARE THERAPY, AND MORTALITY IN CKD REMAINS UNCHANGED. THESE DATA SUGGEST THAT KEY PATHOGENETIC MECHANISMS UNDERLYING CKD PROGRESSION GO UNAFFECTED BY CURRENT TREATMENTS. GROWING EVIDENCE SUGGESTS THAT NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND CKD SHARE COMMON PATHOGENETIC MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS. COMMON NUTRITIONAL CONDITIONS PREDISPOSING TO BOTH NAFLD AND CKD INCLUDE EXCESSIVE FRUCTOSE INTAKE AND VITAMIN D DEFICIENCY. MODULATION OF NUCLEAR TRANSCRIPTION FACTORS REGULATING KEY PATHWAYS OF LIPID METABOLISM, INFLAMMATION, AND FIBROSIS, INCLUDING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AND FARNESOID X RECEPTOR, IS ADVANCING TO STAGE III CLINICAL DEVELOPMENT. THE RELEVANCE OF EPIGENETIC REGULATION IN THE PATHOGENESIS OF NAFLD AND CKD IS ALSO EMERGING, AND MODULATION OF MICRORNA21 IS A PROMISING THERAPEUTIC TARGET. ALTHOUGH SINGLE ANTIOXIDANT SUPPLEMENTATION HAS YIELDED VARIABLE RESULTS, MODULATION OF KEY EFFECTORS OF REDOX REGULATION AND MOLECULAR SENSORS OF INTRACELLULAR ENERGY, NUTRIENT, OR OXYGEN STATUS SHOW PROMISING PRECLINICAL RESULTS. OTHER EMERGING THERAPEUTIC APPROACHES TARGET KEY MEDIATORS OF INFLAMMATION, SUCH AS CHEMOKINES; FIBROGENESIS, SUCH AS GALECTIN-3; OR GUT DYSFUNCTION THROUGH GUT MICROBIOTA MANIPULATION AND INCRETIN-BASED THERAPIES. FURTHERMORE, NAFLD PER SE AFFECTS CKD THROUGH LIPOPROTEIN METABOLISM AND HEPATOKINE SECRETION, AND CONVERSELY, TARGETING THE RENAL TUBULE BY SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS CAN IMPROVE BOTH CKD AND NAFLD. IMPLICATIONS FOR THE TREATMENT OF NAFLD AND CKD ARE DISCUSSED IN LIGHT OF THIS NEW THERAPEUTIC ARMAMENTARIUM. 2016