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 5370 22 RECENT ADVANCES IN UNDERSTANDING OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED AS ANY CONDITION THAT CAUSES REDUCED KIDNEY FUNCTION OVER A PERIOD OF TIME. FIBROSIS, TUBULAR ATROPHY AND INTERSTITIAL INFLAMMATION ARE THE HALLMARK OF PATHOLOGICAL FEATURES IN CKD. REGARDLESS OF INITIAL INSULT, CKD HAS SOME COMMON PATHWAYS LEADING CKD TO END-STAGE KIDNEY DISEASE, INCLUDING HYPOXIA IN THE TUBULOINTERSTITIUM AND PROTEINURIA. RECENT ADVANCES IN GENOME EDITING TECHNOLOGIES AND STEM CELL RESEARCH GIVE GREAT INSIGHTS TO UNDERSTAND THE PATHOGENESIS OF CKD, INCLUDING IDENTIFICATIONS OF THE ORIGINS OF RENAL MYOFIBROBLASTS AND TUBULAR EPITHELIAL CELLS UPON INJURY. ENVIRONMENTAL FACTORS SUCH AS HYPOXIA, OXIDATIVE STRESS, AND EPIGENETIC FACTORS IN RELATION TO CKD ARE ALSO DISCUSSED. 2015 3 3466 25 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 4 2034 23 EPIGENETIC CHANGES IN THE ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. PREVIOUSLY ACUTE KIDNEY INJURY (AKI) HAD BEEN BELIEVED TO BE A TRANSIENT EVENT, AND RECOVERY FROM AKI HAD BEEN THOUGHT TO LEAD TO NO CONSEQUENCES. HOWEVER, RECENT EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT EVEN IF THERE IS COMPLETE RECOVERY OF THE KIDNEY FUNCTION, AKI CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD) AND EVENTUALLY IN END-STAGE KIDNEY DISEASE IN THE LONG TERM. TRANSITION OF AKI TO CKD IS MEDIATED BY MULTIPLE MECHANISMS, INCLUDING ABERRANT CELL CYCLE ARREST AND HYPOXIA. HYPOXIA OF THE KIDNEY IS INDUCED BY RAREFACTION OF THE PERITUBULAR CAPILLARIES AFTER AKI EPISODES, AND INDUCES INFLAMMATION AND FIBROSIS. IT SHOULD ALSO BE NOTED THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO HYPOXIA, AND EPIGENETIC CHANGES INDUCED BY HYPOXIA, CALLED "HYPOXIC MEMORY" CAN EXPLAIN THE AKI-TO-CKD TRANSITION IN THE LONG TERM AFTER COMPLETE RECOVERY FROM THE INITIAL AKI EPISODE. TARGETING HYPOXIA AND SUBSEQUENT EPIGENETIC CHANGES ARE PROMISING STRATEGIES TO BLOCK THE TRANSITION FROM AKI TO CKD. 2017 5 4513 17 MULTI-OMIC APPROACHES TO ACUTE KIDNEY INJURY AND REPAIR. THE KIDNEY HAS A REMARKABLE REGENERATIVE CAPACITY. IN RESPONSE TO ISCHEMIC OR TOXIC INJURY, PROXIMAL TUBULE CELLS CAN PROLIFERATE TO REBUILD DAMAGED TUBULES AND RESTORE KIDNEY FUNCTION. HOWEVER, SEVERE ACUTE KIDNEY INJURY (AKI) OR RECURRENT AKI EVENTS CAN LEAD TO MALADAPTIVE REPAIR AND DISEASE PROGRESSION FROM AKI TO CHRONIC KIDNEY DISEASE (CKD). THE APPLICATION OF SINGLE CELL TECHNOLOGIES HAS IDENTIFIED INJURED PROXIMAL TUBULE CELL STATES WEEKS AFTER AKI, DISTINGUISHED BY A PRO-INFLAMMATORY SENESCENT MOLECULAR SIGNATURE. EPIGENETIC STUDIES HIGHLIGHTED DYNAMIC CHANGES IN THE CHROMATIN LANDSCAPE OF THE KIDNEY FOLLOWING AKI AND DESCRIBED KEY TRANSCRIPTION FACTORS LINKED TO THE AKI RESPONSE. THE INTEGRATION OF MULTI-OMIC TECHNOLOGIES OPENS NEW POSSIBILITIES TO IMPROVE OUR UNDERSTANDING OF AKI AND THE DRIVING FORCES BEHIND THE AKI-TO-CKD TRANSITION, WITH THE ULTIMATE GOAL OF DESIGNING TAILORED DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO IMPROVE AKI OUTCOMES AND PREVENT KIDNEY DISEASE PROGRESSION. 2021 6 5994 24 TGFBETA-INCURRED EPIGENETIC ABERRATIONS OF MIRNA AND DNA METHYLTRANSFERASE SUPPRESS KLOTHO AND POTENTIATE RENAL FIBROSIS. RENAL FIBROSIS IS A COMMON PATHOLOGICAL FEATURE OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS SUCH AS ABERRANT MIRNA AND DNA METHYLATION. KLOTHO IS AN ANTI-AGING AND ANTI-FIBROTIC PROTEIN AND ITS EARLY DECLINE AFTER RENAL INJURY IS REPORTEDLY ASSOCIATED WITH ABERRANT DNA METHYLATION. HOWEVER, THE KEY UPSTREAM PATHOLOGICAL MEDIATORS AND THE MOLECULAR CASCADE LEADING TO EPIGENETIC KLOTHO SUPPRESSION ARE NOT EXCLUSIVELY ESTABLISHED. HERE WE INVESTIGATE THE EPIGENETIC MECHANISM OF KLOTHO DEFICIENCY AND ITS FUNCTIONAL RELEVANCE IN RENAL FIBROGENESIS. FIBROTIC KIDNEYS INDUCED BY UNILATERAL URETERAL OCCLUSION (UUO) DISPLAYED MARKED KLOTHO SUPPRESSION AND THE PROMOTER HYPERMETHYLATION. THESE ABNORMALITIES WERE LIKELY DUE TO DEREGULATED TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) SINCE TGFBETA ALONE CAUSED THE SIMILAR EPIGENETIC ABERRATIONS IN CULTURED RENAL CELLS AND TGFBETA BLOCKADE PREVENTED THE ALTERATIONS IN UUO KIDNEY. FURTHER INVESTIGATION REVEALED THAT TGFBETA ENHANCED DNA METHYLTRANSFERASE (DNMT) 1 AND DNMT3A VIA INHIBITING MIR-152 AND MIR-30A IN BOTH RENAL CELLS AND FIBROTIC KIDNEYS. ACCORDINGLY THE BLOCKADE OF EITHER TGFBETA SIGNALING OR DNMT1/3A ACTIVITIES SIGNIFICANTLY RECOVERED THE KLOTHO LOSS AND ATTENUATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS. MOREOVER, KLOTHO KNOCKDOWN BY RNA INTERFERENCES ABOLISHED THE ANTI-FIBROTIC EFFECTS OF DNMT INHIBITION IN BOTH TGFBETA-TREATED RENAL CELL AND UUO KIDNEY, INDICATING THAT TGFBETA-MEDIATED MIR-152/30A INHIBITIONS, DNMT1/3A ABERRATIONS AND SUBSEQUENT KLOTHO LOSS CONSTITUTE A CRITICAL REGULATORY LOOP THAT ELIMINATES KLOTHO'S ANTI-FIBROTIC ACTIVITIES AND POTENTIATES RENAL FIBROGENESIS. THUS, OUR STUDY ELABORATES A NOVEL EPIGENETIC CASCADE OF RENAL FIBROGENESIS AND REVEALS THE POTENTIAL THERAPEUTIC TARGETS FOR TREATING THE RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. 2017 7 1665 30 DOWNREGULATION OF KIDNEY PROTECTIVE FACTORS BY INFLAMMATION: ROLE OF TRANSCRIPTION FACTORS AND EPIGENETIC MECHANISMS. CHRONIC KIDNEY DISEASE (CKD) IS ASSOCIATED TO AN INCREASED RISK OF DEATH, CKD PROGRESSION, AND ACUTE KIDNEY INJURY (AKI) EVEN FROM EARLY STAGES, WHEN GLOMERULAR FILTRATION RATE (GFR) IS PRESERVED. THE LINK BETWEEN EARLY CKD AND THESE RISKS IS UNCLEAR, SINCE THERE IS NO ACCUMULATION OF UREMIC TOXINS. HOWEVER, PATHOLOGICAL ALBUMINURIA AND KIDNEY INFLAMMATION ARE FREQUENT FEATURES OF EARLY CKD, AND THE PRODUCTION OF KIDNEY PROTECTIVE FACTORS MAY BE DECREASED. INDEED, KLOTHO EXPRESSION IS ALREADY DECREASED IN CKD CATEGORY G1 (NORMAL GFR). KLOTHO HAS ANTI-AGING AND NEPHROPROTECTIVE PROPERTIES, AND DECREASED KLOTHO LEVELS MAY CONTRIBUTE TO INCREASE THE RISK OF DEATH, CKD PROGRESSION, AND AKI. IN THIS REVIEW, WE DISCUSS THE DOWNREGULATION BY MEDIATORS OF INFLAMMATION OF MOLECULES WITH SYSTEMIC AND/OR RENAL LOCAL PROTECTIVE FUNCTIONS, EXEMPLIFIED BY KLOTHO AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA), A TRANSCRIPTION FACTOR THAT PROMOTES MITOCHONDRIAL BIOGENESIS. CYTOKINES SUCH AS TWEAK, TNF-ALPHA, OR TRANSFORMING GROWTH FACTOR -BETA1 PRODUCED LOCALLY DURING KIDNEY INJURY OR RELEASED FROM INFLAMMATORY SITES AT OTHER ORGANS MAY DECREASE KIDNEY EXPRESSION OF KLOTHO AND PGC-1ALPHA OR LEAD TO SUBOPTIMAL RECRUITMENT OF THESE NEPHROPROTECTIVE PROTEINS. TRANSCRIPTION FACTORS (E.G., SMAD3 AND NF-KAPPAB) AND EPIGENETIC MECHANISMS (E.G., HISTONE ACETYLATION OR METHYLATION) CONTRIBUTE TO DOWNREGULATE THE EXPRESSION OF KLOTHO AND/OR PGC-1ALPHA, WHILE HISTONE CROTONYLATION PROMOTES PGC-1ALPHA EXPRESSION. NF-KAPPABIZ FACILITATES THE REPRESSIVE EFFECT OF NF-KAPPAB ON KLOTHO EXPRESSION. A DETAILED UNDERSTANDING OF THESE MEDIATORS MAY CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES TO PREVENT CKD PROGRESSION AND ITS NEGATIVE IMPACT ON MORTALITY AND AKI. 2016 8 5988 26 TGF-BETA/SMAD AND RENAL FIBROSIS. RENAL FIBROSIS IS CHARACTERIZED BY EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM) THAT DISRUPTS AND REPLACES FUNCTIONAL PARENCHYMA, WHICH LEADS TO ORGAN FAILURE. IT IS KNOWN AS THE MAJOR PATHOLOGICAL MECHANISM OF CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH CKD HAS AN IMPACT ON NO LESS THAN 10% OF THE WORLD POPULATION, THERAPEUTIC OPTIONS ARE STILL LIMITED. REGARDLESS OF ETIOLOGY, ELEVATED TGF-BETA LEVELS ARE HIGHLY CORRELATED WITH THE ACTIVATED PRO-FIBROTIC PATHWAYS AND DISEASE PROGRESSION. TGF-BETA, THE KEY DRIVER OF RENAL FIBROSIS, IS INVOLVED IN A DYNAMIC PATHOPHYSIOLOGICAL PROCESS THAT LEADS TO CKD AND END-STAGE RENAL DISEASE (ESRD). IT IS BECOMING CLEAR THAT EPIGENETICS REGULATES RENAL PROGRAMMING, AND THEREFORE, THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. INDEED, RECENT EVIDENCE SHOWS TGF-BETA1/SMAD SIGNALING REGULATES RENAL FIBROSIS VIA EPIGENETIC-CORRELATED MECHANISMS. THIS REVIEW FOCUSES ON THE FUNCTION OF TGF-BETA/SMADS IN RENAL FIBROGENESIS, AND THE ROLE OF EPIGENETICS AS A REGULATOR OF PRO-FIBROTIC GENE EXPRESSION. 2019 9 4381 29 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 10 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 11 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 12 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 13 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 14 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 15 6051 20 THE CONTRIBUTION OF HISTONE CROTONYLATION TO TISSUE HEALTH AND DISEASE: FOCUS ON KIDNEY HEALTH. ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD) ARE THE MOST SEVERE CONSEQUENCES OF KIDNEY INJURY. THEY ARE INTERCONNECTED SYNDROMES AS CKD PREDISPOSES TO AKI AND AKI MAY ACCELERATE CKD PROGRESSION. DESPITE THEIR GROWING IMPACT ON THE GLOBAL BURDEN OF DISEASE, THERE IS NO SATISFACTORY TREATMENT FOR AKI AND CURRENT THERAPEUTIC APPROACHES TO CKD REMAIN SUBOPTIMAL. RECENT RESEARCH HAS FOCUSED ON THE THERAPEUTIC TARGET POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION, INCLUDING NON-CODING RNAS AND THE COVALENT MODIFICATIONS OF HISTONES AND DNA. INDEED, SEVERAL DRUGS TARGETING HISTONE MODIFICATIONS ARE IN CLINICAL USE OR UNDERGOING CLINICAL TRIALS. ACYL-LYSINE HISTONE MODIFICATIONS (E.G. METHYLATION, ACETYLATION, AND CROTONYLATION) HAVE MODULATED EXPERIMENTAL KIDNEY INJURY. MOST RECENTLY, INCREASED HISTONE LYSINE CROTONYLATION (KCR) WAS OBSERVED DURING EXPERIMENTAL AKI AND COULD BE REPRODUCED IN CULTURED TUBULAR CELLS EXPOSED TO INFLAMMATORY STRESS TRIGGERED BY THE CYTOKINE TWEAK. THE DEGREE OF KIDNEY HISTONE CROTONYLATION WAS MODULATED BY CROTONATE AVAILABILITY AND CROTONATE SUPPLEMENTATION PROTECTED FROM NEPHROTOXIC AKI. WE NOW REVIEW THE FUNCTIONAL RELEVANCE OF HISTONE CROTONYLATION IN KIDNEY DISEASE AND OTHER PATHOPHYSIOLOGICAL CONTEXTS, AS WELL AS THE IMPLICATIONS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES. THESE STUDIES PROVIDE INSIGHTS INTO THE OVERALL ROLE OF HISTONE CROTONYLATION IN HEALTH AND DISEASE. 2020 16 4016 25 LOW-DOSE HYDRALAZINE PREVENTS FIBROSIS IN A MURINE MODEL OF ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) AND PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD) ARE INTRINSICALLY TIED SYNDROMES. IN THIS REGARD, THE ACUTELY INJURED KIDNEY OFTEN DOES NOT ACHIEVE ITS FULL REGENERATIVE CAPACITY AND AKI DIRECTLY TRANSITIONS INTO PROGRESSIVE CKD ASSOCIATED WITH TUBULOINTERSTITIAL FIBROSIS. UNDERLYING MECHANISMS OF SUCH AKI-TO-CKD PROGRESSION ARE STILL INCOMPLETELY UNDERSTOOD AND SPECIFIC THERAPEUTIC INTERVENTIONS ARE STILL ELUSIVE. BECAUSE EPIGENETIC MODIFICATIONS PLAY A ROLE IN MAINTAINING TISSUE FIBROSIS, WE USED A MURINE MODEL OF ISCHEMIA-REPERFUSION INJURY TO DETERMINE WHETHER ABERRANT PROMOTER METHYLATION OF RASAL1 CONTRIBUTES CAUSALLY TO THE SWITCH BETWEEN PHYSIOLOGICAL REGENERATION AND TUBULOINTERSTITIAL FIBROGENESIS, A HALLMARK OF AKI-TO-CKD PROGRESSION. IT IS KNOWN THAT THE ANTIHYPERTENSIVE DRUG HYDRALAZINE HAS DEMETHYLATING ACTIVITY, AND THAT ITS OPTIMUM DEMETHYLATING ACTIVITY OCCURS AT CONCENTRATIONS BELOW BLOOD PRESSURE-LOWERING DOSES. ADMINISTRATION OF LOW-DOSE HYDRALAZINE EFFECTIVELY INDUCED EXPRESSION OF HYDROXYLASE TET3, WHICH CATALYZED RASAL1 HYDROXYMETHYLATION AND SUBSEQUENT RASAL1 PROMOTER DEMETHYLATION. HYDRALAZINE-INDUCED CPG PROMOTER DEMETHYLATION SUBSEQUENTLY ATTENUATED RENAL FIBROSIS AND PRESERVED EXCRETORY RENAL FUNCTION INDEPENDENT OF ITS BLOOD PRESSURE-LOWERING EFFECTS. IN COMPARISON, RASAL1 DEMETHYLATION AND INHIBITION OF TUBULOINTERSTITIAL FIBROSIS WAS NOT DETECTED UPON ADMINISTRATION OF THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR RAMIPRIL IN THIS MODEL. THUS, RASAL1 PROMOTER METHYLATION AND SUBSEQUENT TRANSCRIPTIONAL RASAL1 SUPPRESSION PLAYS A CAUSAL ROLE IN AKI-TO-CKD PROGRESSION. 2017 17 3885 31 KIDNEY FIBROSIS: FROM MECHANISMS TO THERAPEUTIC MEDICINES. CHRONIC KIDNEY DISEASE (CKD) IS ESTIMATED TO AFFECT 10-14% OF GLOBAL POPULATION. KIDNEY FIBROSIS, CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION LEADING TO SCARRING, IS A HALLMARK MANIFESTATION IN DIFFERENT PROGRESSIVE CKD; HOWEVER, AT PRESENT NO ANTIFIBROTIC THERAPIES AGAINST CKD EXIST. KIDNEY FIBROSIS IS IDENTIFIED BY TUBULE ATROPHY, INTERSTITIAL CHRONIC INFLAMMATION AND FIBROGENESIS, GLOMERULOSCLEROSIS, AND VASCULAR RAREFACTION. FIBROTIC NICHE, WHERE ORGAN FIBROSIS INITIATES, IS A COMPLEX INTERPLAY BETWEEN INJURED PARENCHYMA (LIKE TUBULAR CELLS) AND MULTIPLE NON-PARENCHYMAL CELL LINEAGES (IMMUNE AND MESENCHYMAL CELLS) LOCATED SPATIALLY WITHIN SCARRING AREAS. ALTHOUGH THE MECHANISMS OF KIDNEY FIBROSIS ARE COMPLICATED DUE TO THE KINDS OF CELLS INVOLVED, WITH THE HELP OF SINGLE-CELL TECHNOLOGY, MANY KEY QUESTIONS HAVE BEEN EXPLORED, SUCH AS WHAT KIND OF RENAL TUBULES ARE PROFIBROTIC, WHERE MYOFIBROBLASTS ORIGINATE, WHICH IMMUNE CELLS ARE INVOLVED, AND HOW CELLS COMMUNICATE WITH EACH OTHER. IN ADDITION, GENETICS AND EPIGENETICS ARE DEEPER MECHANISMS THAT REGULATE KIDNEY FIBROSIS. AND THE REVERSIBLE NATURE OF EPIGENETIC CHANGES INCLUDING DNA METHYLATION, RNA INTERFERENCE, AND CHROMATIN REMODELING, GIVES AN OPPORTUNITY TO STOP OR REVERSE KIDNEY FIBROSIS BY THERAPEUTIC STRATEGIES. MORE MARKETED (E.G., RAS BLOCKAGE, SGLT2 INHIBITORS) HAVE BEEN DEVELOPED TO DELAY CKD PROGRESSION IN RECENT YEARS. FURTHERMORE, A BETTER UNDERSTANDING OF RENAL FIBROSIS IS ALSO FAVORED TO DISCOVER BIOMARKERS OF FIBROTIC INJURY. IN THE REVIEW, WE UPDATE RECENT ADVANCES IN THE MECHANISM OF RENAL FIBROSIS AND SUMMARIZE NOVEL BIOMARKERS AND ANTIFIBROTIC TREATMENT FOR CKD. 2023 18 221 23 ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. BACKGROUND: ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY RENAL RECOVERY, IS A RISK FACTOR FOR THE FUTURE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD). IN THE PREVIOUS YEARS, NOVEL INSIGHTS IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION SUGGESTED A CAUSAL LINK BETWEEN AKI AND CKD DUE TO A MALADAPTIVE REPAIR AFTER SEVERE AND REPEATED INJURY. SUMMARY: SEVERAL PATHOLOGICAL MECHANISMS HAVE BEEN PROPOSED TO CONTRIBUTE TO THE PROGRESSION OF AKI AND TRANSITION TO CKD/ESRD INCLUDING HYPOXIA AND MICROVASCULAR RAREFACTION, ALTERATIONS OF RENAL RESIDENT CELL PHENOTYPES AND FUNCTIONS, CELL CYCLE ARREST IN THE G2/M PHASE, PERSISTENT CHRONIC INFLAMMATION, AND DEVELOPMENT OF INTERSTITIAL FIBROSIS, MITOCHONDRIAL FRAGMENTATION, EPIGENETIC CHANGES, ACTIVATION OF RENIN-ANGIOTENSIN SYSTEM (RAS), CELL AND TISSUE SENESCENCE. FURTHERMORE, SEVERAL CLINICAL FACTORS HAVE BEEN IDENTIFIED SUCH AS SEVERITY OF AKI, AGE, AND COMORBIDITIES. THE IDENTIFICATION OF AKI-TO-CKD BIOMARKERS COULD IMPROVE THE EARLY IDENTIFICATION OF AKI PATIENTS WITH HIGHER RISK FOR CKD PROGRESSION. HOWEVER, ALTHOUGH OUR UNDERSTANDING IN THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION IS SIGNIFICANTLY IMPROVED, NO NOVEL INTERVENTION HAS BEEN VALIDATED. POTENTIAL THERAPEUTIC APPROACHES TO TREAT AKI AND BLOCK THE TRANSITION TO CKD/ESRD HAVE BEEN RECENTLY REPORTED, BUT THEY NEED FURTHER VALIDATIONS. KEY MESSAGES: MALADAPTIVE REPAIR AFTER AKI IS STRONGLY ASSOCIATED TO THE DEVELOPMENT OF CKD AND LONG-TERM CONSEQUENCES. THE PROMPT IDENTIFICATION OF PATIENTS AT HIGHER RISK FOR LATE CKD PROGRESSION AND THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS REMAIN CRITICAL RESEARCH GOALS. 2018 19 6299 29 THE PROXIMAL TUBULE IS THE PRIMARY TARGET OF INJURY AND PROGRESSION OF KIDNEY DISEASE: ROLE OF THE GLOMERULOTUBULAR JUNCTION. THERE IS AN ALARMING GLOBAL INCREASE IN THE INCIDENCE OF END-STAGE KIDNEY DISEASE, FOR WHICH EARLY BIOMARKERS AND EFFECTIVE TREATMENT OPTIONS ARE LACKING. LARGELY BASED ON THE HISTOLOGY OF THE END-STAGE KIDNEY AND ON THE MODEL OF UNILATERAL URETERAL OBSTRUCTION, CURRENT INVESTIGATION IS FOCUSED ON THE PATHOGENESIS OF RENAL INTERSTITIAL FIBROSIS AS A CENTRAL MECHANISM IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). IT IS NOW RECOGNIZED THAT CUMULATIVE EPISODES OF ACUTE KIDNEY INJURY (AKI) CAN LEAD TO CKD, AND, CONVERSELY, CKD IS A RISK FACTOR FOR AKI. BASED ON RECENT AND HISTORIC STUDIES, THIS REVIEW SHIFTS ATTENTION FROM THE GLOMERULUS AND INTERSTITIUM TO THE PROXIMAL TUBULE AS THE PRIMARY SENSOR AND EFFECTOR IN THE PROGRESSION OF CKD AS WELL AS AKI. PACKED WITH MITOCHONDRIA AND DEPENDENT ON OXIDATIVE PHOSPHORYLATION, THE PROXIMAL TUBULE IS PARTICULARLY VULNERABLE TO INJURY (OBSTRUCTIVE, ISCHEMIC, HYPOXIC, OXIDATIVE, METABOLIC), RESULTING IN CELL DEATH AND ULTIMATELY IN THE FORMATION OF ATUBULAR GLOMERULI. ANIMAL MODELS OF HUMAN GLOMERULAR AND TUBULAR DISORDERS HAVE PROVIDED EVIDENCE FOR A BROAD REPERTOIRE OF MORPHOLOGICAL AND FUNCTIONAL RESPONSES OF THE PROXIMAL TUBULE, REVEALING PROCESSES OF DEGENERATION AND REPAIR THAT MAY LEAD TO NEW THERAPEUTIC STRATEGIES. MOST PROMISING ARE STUDIES THAT ENCOMPASS THE ENTIRE LIFE CYCLE FROM FETUS TO SENESCENCE, RECOGNIZING EPIGENETIC FACTORS. THE APPLICATION OF TECHNIQUES IN MOLECULAR CHARACTERIZATION OF TUBULE SEGMENTS AND THE DEVELOPMENT OF HUMAN KIDNEY ORGANOIDS MAY PROVIDE NEW INSIGHTS INTO THE MAMMALIAN KIDNEY SUBJECTED TO STRESS OR INJURY, LEADING TO BIOMARKERS OF EARLY CKD AND NEW THERAPIES. 2016 20 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