1 5363 65 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 2 6575 29 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 3 6648 25 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 4 4137 22 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 5 2121 32 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 4971 26 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 7 1832 29 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 8 2972 26 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 9 6075 29 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 10 5300 25 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 11 1536 23 DNA METHYLATION ENZYMES IN THE KIDNEYS OF MALE AND FEMALE BTBR OB/OB MICE. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF THE END-STAGE RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS CONTRIBUTE TO ALTERATIONS IN GENE EXPRESSION AND THE DEVELOPMENT OF DKD. THIS STUDY AIMED TO SHOW AN EXPRESSION PROFILE OF KEY DNA (DE)METHYLATION ENZYMES (DNMT, TET PROTEINS) AND THEIR DIFFERENCES BETWEEN SEXES UNDER OBESITY AND DIABETIC CONDITION. MALE AND FEMALE BLACK AND TAN BRACHYURY (BTBR) OB/OB MICE AND THEIR CORRESPONDING WILD-TYPE LITTERMATES (BTBR WT) WERE STUDIED UNTIL 16 WEEKS OF AGE. METABOLIC PARAMETERS, KIDNEY MORPHOPHYSIOLOGY AND THE EXPRESSION OF FIBROTIC MARKERS AND EPIGENETIC ENZYMES WERE STUDIED IN WHOLE KIDNEY TISSUE OR SPECIFICALLY IN THE GLOMERULUS. THE RESULTS SHOWED SEXUAL DIMORPHISM IN THE DEVELOPMENT OF METABOLIC DISEASE AND IN KIDNEY MORPHOPHYSIOLOGY. FEMALE MICE HAVE A DIFFERENT PROFILE OF DNMTS EXPRESSION IN BOTH WT AND OBESE/DIABETIC CONDITION. FURTHERMORE, METABOLIC CONDITION NEGATIVELY MODULATED THE GLOMERULAR EXPRESSION OF TET1 AND TET3 ONLY IN FEMALES. TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY THAT SHOWS A KIDNEY PROFILE OF THE EXPRESSION OF KEY (DE)METHYLATION ENZYMES, DNMTS AND TETS, IN THE BTBR OB/OB EXPERIMENTAL MODEL OF DKD AND ITS ASSOCIATION WITH SEX. THE KNOWLEDGE OF THIS EPIGENETIC PROFILE MAY HELP FUTURE RESEARCH TO UNDERSTAND THE PATHOPHYSIOLOGY OF DKD IN MALES AND FEMALES. 2023 12 5442 19 RENIN-ANGIOTENSIN BLOCKADE RESETS PODOCYTE EPIGENOME THROUGH KRUPPEL-LIKE FACTOR 4 AND ATTENUATES PROTEINURIA. PROTEINURIA IS A CENTRAL COMPONENT OF CHRONIC KIDNEY DISEASE AND AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. KIDNEY PODOCYTES HAVE AN ESSENTIAL ROLE AS A FILTRATION BARRIER AGAINST PROTEINURIA. KRUPPEL-LIKE FACTOR 4 (KLF4) IS EXPRESSED IN PODOCYTES AND DECREASED IN GLOMERULAR DISEASES LEADING TO METHYLATION OF THE NEPHRIN PROMOTER, DECREASED NEPHRIN EXPRESSION AND PROTEINURIA. TREATMENT WITH AN ANGIOTENSIN RECEPTOR BLOCKER (ARB) REDUCED METHYLATION OF THE NEPHRIN PROMOTER IN MURINE GLOMERULI OF AN ADRIAMYCIN NEPHROPATHY MODEL WITH RECOVERY OF KLF4 EXPRESSION AND A DECREASE IN ALBUMINURIA. IN PODOCYTE-SPECIFIC KLF4 KNOCKOUT MICE, THE EFFECT OF ARB ON ALBUMINURIA AND THE NEPHRIN PROMOTER METHYLATION WAS ATTENUATED. IN CULTURED HUMAN PODOCYTES, ANGIOTENSIN II REDUCED KLF4 EXPRESSION AND CAUSED METHYLATION OF THE NEPHRIN PROMOTER WITH DECREASED NEPHRIN EXPRESSION. IN PATIENTS, NEPHRIN PROMOTER METHYLATION WAS INCREASED IN PROTEINURIC KIDNEY DISEASES WITH DECREASED KLF4 AND NEPHRIN EXPRESSION. KLF4 EXPRESSION IN ARB-TREATED PATIENTS WAS HIGHER IN PATIENTS WITH THAN WITHOUT ARB TREATMENT. THUS, ANGIOTENSIN II CAN MODULATE EPIGENETIC REGULATION IN PODOCYTES AND ARB INHIBITS THESE ACTIONS IN PART VIA KLF4 IN PROTEINURIC KIDNEY DISEASES. THIS STUDY PROVIDES A NEW CONCEPT THAT RENIN-ANGIOTENSIN SYSTEM BLOCKADE CAN EXERT THERAPEUTIC EFFECTS THROUGH EPIGENETIC MODULATION OF THE KIDNEY GENE EXPRESSION. 2015 13 199 26 ACTIVATED HISTONE ACETYLTRANSFERASE P300/CBP-RELATED SIGNALLING PATHWAYS MEDIATE UP-REGULATION OF NADPH OXIDASE, INFLAMMATION, AND FIBROSIS IN DIABETIC KIDNEY. ACCUMULATING EVIDENCE IMPLICATES THE HISTONE ACETYLATION-BASED EPIGENETIC MECHANISMS IN THE PATHOETIOLOGY OF DIABETES-ASSOCIATED MICRO-/MACROVASCULAR COMPLICATIONS. DIABETIC KIDNEY DISEASE (DKD) IS A PROGRESSIVE CHRONIC INFLAMMATORY MICROVASCULAR DISORDER ULTIMATELY LEADING TO GLOMERULOSCLEROSIS AND KIDNEY FAILURE. WE HYPOTHESIZED THAT HISTONE ACETYLTRANSFERASE P300/CBP MAY BE INVOLVED IN MEDIATING DIABETES-ACCELERATED RENAL DAMAGE. IN THIS STUDY, WE AIMED AT INVESTIGATING THE POTENTIAL ROLE OF P300/CBP IN THE UP-REGULATION OF RENAL NADPH OXIDASE (NOX), REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, INFLAMMATION, AND FIBROSIS IN DIABETIC MICE. DIABETIC C57BL/6J MICE WERE RANDOMIZED TO RECEIVE 10 MG/KG C646, A SELECTIVE P300/CBP INHIBITOR, OR ITS VEHICLE FOR 4 WEEKS. WE FOUND THAT IN THE KIDNEY OF C646-TREATED DIABETIC MICE, THE LEVEL OF H3K27AC, AN EPIGENETIC MARK OF ACTIVE GENE EXPRESSION, WAS SIGNIFICANTLY REDUCED. PHARMACOLOGICAL INHIBITION OF P300/CBP SIGNIFICANTLY DOWN-REGULATED THE DIABETES-INDUCED ENHANCED EXPRESSION OF NOX SUBTYPES, PRO-INFLAMMATORY, AND PRO-FIBROTIC MOLECULES IN THE KIDNEY OF MICE, AND THE GLOMERULAR ROS OVERPRODUCTION. OUR STUDY PROVIDES EVIDENCE THAT THE ACTIVATION OF P300/CBP ENHANCES ROS PRODUCTION, POTENTIALLY GENERATED BY UP-REGULATED NOX, INFLAMMATION, AND THE PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN THE DIABETIC KIDNEY. THE DATA SUGGEST THAT P300/CBP-PHARMACOLOGICAL INHIBITORS MAY BE ATTRACTIVE TOOLS TO MODULATE DIABETES-ASSOCIATED PATHOLOGICAL PROCESSES TO EFFICIENTLY REDUCE THE BURDEN OF DKD. 2021 14 1983 28 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 15 3913 25 LIFESTYLE MODIFICATIONS AND NUTRITIONAL AND THERAPEUTIC INTERVENTIONS IN DELAYING THE PROGRESSION OF CHRONIC KIDNEY DISEASE: A REVIEW. CHRONIC KIDNEY DISEASE (CKD) IS A DEBILITATING PROGRESSIVE ILLNESS THAT AFFECTS MORE THAN 10% OF THE WORLD'S POPULATION. IN THIS LITERATURE REVIEW, WE DISCUSSED THE ROLES OF NUTRITIONAL INTERVENTIONS, LIFESTYLE MODIFICATIONS, HYPERTENSION (HTN) AND DIABETES MELLITUS (DM) CONTROL, AND MEDICATIONS IN DELAYING THE PROGRESSION OF CKD. WALKING, WEIGHT LOSS, LOW-PROTEIN DIET (LPD), ADHERENCE TO THE ALTERNATE MEDITERRANEAN (AMED) DIET, AND ALTERNATIVE HEALTHY EATING INDEX (AHEI)-2010 SLOW THE PROGRESSION OF CKD. HOWEVER, SMOKING AND BINGE ALCOHOL DRINKING INCREASE THE RISK OF CKD PROGRESSION. IN ADDITION, HYPERGLYCEMIA, ALTERED LIPID METABOLISM, LOW-GRADE INFLAMMATION, OVER-ACTIVATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS), AND OVERHYDRATION (OH) INCREASE DIABETIC CKD PROGRESSION. THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES (KDIGO) GUIDELINES RECOMMEND BLOOD PRESSURE (BP) CONTROL OF <140/90 MMHG IN PATIENTS WITHOUT ALBUMINURIA AND <130/80 MMHG IN PATIENTS WITH ALBUMINURIA TO PREVENT CKD PROGRESSION. MEDICAL THERAPIES AIM TO TARGET EPIGENETIC ALTERATIONS, FIBROSIS, AND INFLAMMATION. CURRENTLY, RAAS BLOCKADE, SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITORS, PENTOXIFYLLINE, AND FINERENONE ARE APPROVED FOR MANAGING CKD. IN ADDITION, ACCORDING TO THE COMPLETED STUDY OF DIABETIC NEPHROPATHY WITH ATRASENTAN (SONAR), ATRASENTAN, AN ENDOTHELIN RECEPTOR ANTAGONIST (ERA), DECREASED THE RISK OF RENAL EVENTS IN DIABETIC CKD PATIENTS. HOWEVER, ONGOING TRIALS ARE STUDYING THE ROLE OF OTHER AGENTS IN SLOWING THE PROGRESSION OF CKD. 2023 16 273 26 AGE-INDUCED SUPPRESSION OF EZH2 MEDIATES INJURY OF PODOCYTES BY REDUCING H3K27ME3. BACKGROUND: CHRONIC HYPERGLYCEMIA, A PIVOTAL FEATURE OF DIABETES MELLITUS (DM), INITIATES THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) AND THE DYSREGULATION OF EPIGENETIC MECHANISMS, WHICH MAY CAUSE INJURY TO RENAL PODOCYTES, A CENTRAL FEATURE OF DIABETIC KIDNEY DISEASE (DKD). PREVIOUS DATA OF OUR GROUP SHOWED THAT AGES SIGNIFICANTLY REDUCE THE EXPRESSION OF NIPP1 (NUCLEAR INHIBITOR OF PROTEIN PHOSPHATASE 1) IN PODOCYTES IN VITRO AS WELL AS IN HUMAN AND MURINE DKD. NIPP1 WAS SHOWN BY OTHERS TO INTERACT WITH ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE REPRESSIVE METHYLATION OF H3K27ME3 ON HISTONE 3. THEREFORE, WE HYPOTHESIZED THAT AGES CAN DIRECTLY INDUCE EPIGENETIC CHANGES IN PODOCYTES. METHODS: WE ANALYZED THE RELEVANCE OF AGES ON EZH2 EXPRESSION AND ACTIVITY IN A MURINE PODOCYTE CELL LINE. CELLS WERE TREATED WITH 5 MG/ML GLYCATED BSA FOR 24 H. TO DETERMINE THE MEANING OF EZH2 SUPPRESSION, EZH2 ACTIVITY WAS INHIBITED BY INCUBATING THE CELLS WITH THE PHARMACOLOGICAL METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A; EZH2 EXPRESSION WAS REPRESSED WITH SIRNA. MRNA EXPRESSION WAS ANALYZED WITH REAL-TIME PCR, AND PROTEIN EXPRESSION WITH WESTERN BLOT. EZH2 EXPRESSION AND LEVEL OF H3K27 TRIMETHYLATION IN PODOCYTES OF DIABETIC DB/DB MICE, A MOUSE MODEL FOR TYPE 2 DM, WERE ANALYZED USING IMMUNOFLUORESCENCE. RESULTS: OUR DATA DEMONSTRATED THAT AGES DECREASE EZH2 EXPRESSION IN PODOCYTES AND CONSEQUENTLY REDUCE H3K27ME3. THIS SUPPRESSION OF EZH2 MIMICKED THE AGE EFFECTS AND CAUSED AN UPREGULATED EXPRESSION OF PATHOLOGICAL FACTORS THAT CONTRIBUTE TO PODOCYTE INJURY IN DKD. IN ADDITION, ANALYSES OF DB/DB MICE SHOWED SIGNIFICANTLY REDUCED H3K27ME3 AND EZH2 EXPRESSION IN PODOCYTES. MOREOVER, THE SUPPRESSION OF NIPP1 AND EZH2 SHOWED SIMILAR EFFECTS REGARDING PODOCYTE INJURY. CONCLUSIONS: OUR STUDIES PROVIDE A NOVEL PATHWAY HOW AGES CONTRIBUTE TO PODOCYTE INJURY AND THE FORMATION OF THE SO-CALLED METABOLIC MEMORY IN DKD. 2020 17 2555 18 EPIGENETICS IN RENAL DISEASES. WITH AGING, PREVALENCE OF OBESITY, HYPERTENSION, DIABETES AND RENAL DISEASES HAVE INCREASED GLOBALLY. OVER THE LAST TWO DECADES, THE PREVALENCE OF RENAL DISEASES HAS BEEN INTENSELY INCREASING. RENAL DISEASE AND RENAL PROGRAMMING ARE REGULATED BY EPIGENETIC MODIFICATIONS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS. ENVIRONMENTAL FACTORS HAVE SIGNIFICANT ROLE IN THE PATHOPHYSIOLOGY OF RENAL DISEASE PROGRESSION. UNDERSTANDING THE POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION MAY BE USEFUL IN RENAL DISEASE PROGNOSIS, DIAGNOSIS AND PROVIDES NOVEL THERAPEUTIC MEASURES. IN A NUTSHELL, THIS CHAPTER TALKS ABOUT THE ROLE OF EPIGENETIC MECHANISMS-DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNA IN DIFFERENT RENAL DISEASES. THESE INCLUDE DIABETIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, RENAL FIBROSIS, ETC. 2023 18 1274 22 DACH1 PROTECTS PODOCYTES FROM EXPERIMENTAL DIABETIC INJURY AND MODULATES PTIP-H3K4ME3 ACTIVITY. DACHSHUND HOMOLOG 1 (DACH1), A KEY CELL-FATE DETERMINANT, REGULATES TRANSCRIPTION BY DNA SEQUENCE-SPECIFIC BINDING. WE IDENTIFIED DIMINISHED DACH1 EXPRESSION IN A LARGE-SCALE SCREEN FOR MUTATIONS THAT CONVERT INJURY-RESISTANT PODOCYTES INTO INJURY-SUSCEPTIBLE PODOCYTES. IN DIABETIC KIDNEY DISEASE (DKD) PATIENTS, PODOCYTE DACH1 EXPRESSION LEVELS ARE DIMINISHED, A CONDITION THAT STRONGLY CORRELATES WITH POOR CLINICAL OUTCOMES. GLOBAL DACH1 KO MICE MANIFEST RENAL HYPOPLASIA AND DIE PERINATALLY. PODOCYTE-SPECIFIC DACH1 KO MICE, HOWEVER, MAINTAIN NORMAL GLOMERULAR ARCHITECTURE AT BASELINE, BUT RAPIDLY EXHIBIT PODOCYTE INJURY AFTER DIABETES ONSET. FURTHERMORE, PODOCYTE-SPECIFIC AUGMENTATION OF DACH1 EXPRESSION IN MICE PROTECTS FROM DKD. COMBINED RNA SEQUENCING AND IN SILICO PROMOTER ANALYSIS REVEAL CONVERSELY OVERLAPPING GLOMERULAR TRANSCRIPTOMIC SIGNATURES BETWEEN PODOCYTE-SPECIFIC DACH1 AND PAX TRANSACTIVATION-DOMAIN INTERACTING PROTEIN (PTIP) KO MICE, WITH UPREGULATED GENES POSSESSING HIGHER-THAN-EXPECTED NUMBERS OF PROMOTER DACH1-BINDING SITES. PTIP, AN ESSENTIAL COMPONENT OF THE ACTIVATING HISTONE H3 LYSINE 4 TRIMETHYLATION (H3K4ME3) COMPLEX, INTERACTS WITH DACH1 AND IS RECRUITED BY DACH1 TO ITS PROMOTER-BINDING SITES. DACH1-PTIP RECRUITMENT REPRESSES TRANSCRIPTION AND REDUCES PROMOTER H3K4ME3 LEVELS. DACH1 KNOCKDOWN IN PODOCYTES COMBINED WITH HYPERGLYCEMIA TRIGGERS TARGET GENE UPREGULATION AND INCREASES PROMOTER H3K4ME3. THESE FINDINGS REVEAL THAT IN DKD, DIMINISHED DACH1 EXPRESSION ENHANCES PODOCYTE INJURY VULNERABILITY VIA EPIGENETIC DEREPRESSION OF ITS TARGET GENES. 2021 19 2579 24 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 20 4433 19 MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS OF DIABETES MELLITUS - A COMPREHENSIVE REVIEW. DIABETES IS A CHRONIC DISEASE, CHARACTERIZED BY HYPERGLYCEMIA, WHICH REFERS TO THE ELEVATED LEVELS OF GLUCOSE IN THE BLOOD, DUE TO THE INABILITY OF THE BODY TO PRODUCE OR USE INSULIN EFFECTIVELY. CHRONIC HYPERGLYCEMIA LEVELS LEAD TO MACROVASCULAR AND MICROVASCULAR COMPLICATIONS. THE MACROVASCULAR COMPLICATIONS CONSIST OF PERIPHERAL ARTERY DISEASE (PAD), CARDIOVASCULAR DISEASES (CVD) AND CEREBROVASCULAR DISEASES, WHILE THE MICROVASCULAR COMPLICATIONS COMPRISE OF DIABETIC MICROANGIOPATHY, DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY AND DIABETIC NEUROPATHY. VASCULAR ENDOTHELIAL DYSFUNCTION PLAYS A CRUCIAL ROLE IN MEDIATING BOTH MACROVASCULAR AND MICROVASCULAR COMPLICATIONS UNDER HYPERGLYCEMIC CONDITIONS. IN DIABETIC MICROVASCULATURE, THE INTRACELLULAR HYPERGLYCEMIA CAUSES DAMAGE TO THE VASCULAR ENDOTHELIUM THROUGH - (I) ACTIVATION OF FOUR BIOCHEMICAL PATHWAYS, NAMELY THE POLYOL PATHWAY, PROTEIN KINASE C (PKC) PATHWAY, ADVANCED GLYCATION END PRODUCTS (AGE) PATHWAY AND HEXOSAMINE PATHWAY, ALL OF WHICH COMMUTES GLUCOSE AND ITS INTERMEDIATES LEADING TO OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DYSREGULATION OF GROWTH FACTORS AND CYTOKINES, (III) EPIGENETIC CHANGES WHICH CONCERN THE CHANGES IN DNA AS A RESPONSE TO INTRACELLULAR CHANGES, AND (IV) ABNORMALITIES IN NON-CODING RNAS, SPECIFICALLY MICRORNAS. THIS REVIEW WILL FOCUS ON GAINING AN UNDERSTANDING OF THE MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS IN DIABETES MELLITUS, TO INCREASE OUR UNDERSTANDING TOWARDS THE DEVELOPMENT OF NEW MECHANISTIC THERAPEUTIC STRATEGIES TO PREVENT OR TREAT DIABETES-INDUCED VASCULAR COMPLICATIONS. 2020