1 4381 117 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 2 4513 28 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 3 1894 40 ENDOTHELIAL CELL SENESCENCE AND INFLAMMAGING: MICRORNAS AS BIOMARKERS AND INNOVATIVE THERAPEUTIC TOOLS. AGING IS ACCOMPANIED BY A PROGRESSIVE DECLINE OF ENDOTHELIAL FUNCTION AND A PROGRESSIVE DRIFT TOWARD A SYSTEMIC PRO-INFLAMMATORY STATUS THAT HAS BEEN DESIGNATED "INFLAMMAGING". BOTH PHENOMENA ARE ACCELERATED AND EXACERBATED IN PATIENTS WITH THE MOST COMMON AGE-RELATED DISEASES (ARDS), INCLUDING CANCER. THE FINDING THAT CHRONIC CELL STRESS ACTIVATES A PRO-INFLAMMATORY PROGRAM LEADING TO ACQUISITION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND TO THE PROPAGATION OF SENESCENCE TO SURROUNDING CELLS THROUGH THE SECRETOME, SUGGESTS THAT CELL SENESCENCE MAY HAVE A ROLE IN BOTH PROCESSES. HERE WE: I) DESCRIBE THE ROLE OF CELL SENESCENCE IN ENDOTHELIAL DYSFUNCTION, II) EMPHASIZE THE CONTRIBUTION OF THE ENDOTHELIAL CELL SASP TO INFLAMMAGING, AND III) SUGGEST THAT SELECTIVE REMOVAL OF SENESCENT ENDOTHELIAL CELLS MAY NOT ONLY HINDER SUCH HARMFUL PROCESSES, BUT ALSO REDUCE THE RISK OF DEVELOPING ARDS AND THEIR COMPLICATIONS. ALTHOUGH IN VIVO DETECTION AND TARGETING OF SENESCENT ENDOTHELIAL CELLS ARE STILL BEING INVESTIGATED, IT IS LIKELY THAT THERAPEUTIC STRATEGIES BASED ON ANTIOXIDANT AND ANTI-INFLAMMATORY COMPOUNDS WOULD INVOLVE GENERALIZED ANTI-AGING EFFECTS ALSO BENEFITING ENDOTHELIAL CELLS. MICRORNA (MIRNAS) - SINGLE-STRANDED, NON-CODING RNAS EXPRESSED BY ALL LIVING CELLS AND INVOLVED IN THE EPIGENETIC MODULATION OF ALL TRANSCRIPTIONAL PROGRAMS - MAY CONSTITUTE AN INNOVATIVE, VALUABLE TOOL TO DETECT AND TARGET SENESCENT ENDOTHELIAL CELLS AND TO DEVISE TREATMENTS THAT CAN SLOW DOWN THE PRO-INFLAMMATORY PROGRAM ACTIVATED IN SENESCENT ENDOTHELIAL CELLS. 2016 4 6451 40 THERAPIES TARGETING EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. ACUTE KIDNEY INJURY (AKI) WAS PREVIOUSLY THOUGHT TO BE A MERELY TRANSIENT EVENT; HOWEVER, RECENT EPIDEMIOLOGICAL EVIDENCE SUPPORTS THE EXISTENCE OF A CAUSAL RELATIONSHIP BETWEEN AKI EPISODES AND SUBSEQUENT PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION IS NOT FULLY UNDERSTOOD, IT IS MEDIATED BY THE INTERPLAY AMONG MULTIPLE COMPONENTS OF THE KIDNEY INCLUDING TUBULAR EPITHELIAL CELLS, ENDOTHELIAL CELLS, PERICYTES, INFLAMMATORY CELLS, AND MYOFIBROBLASTS. EPIGENETIC ALTERATIONS INCLUDING HISTONE MODIFICATION, DNA METHYLATION, NON-CODING RNAS, AND CHROMATIN CONFORMATIONAL CHANGES, ARE ALSO EXPECTED TO BE LARGELY INVOLVED IN THE PATHOPHYSIOLOGY AS A "MEMORY" OF THE INITIAL INJURY THAT CAN PERSIST AND PREDISPOSE TO CHRONIC PROGRESSION OF FIBROSIS. EACH EPIGENETIC MODIFICATION HAS A GREAT POTENTIAL AS A THERAPEUTIC TARGET OF AKI-TO-CKD TRANSITION; TIMELY AND TARGET-SPECIFIC EPIGENETIC INTERVENTIONS TO THE VARIOUS TEMPORAL STAGES OF AKI-TO-CKD TRANSITION WILL BE THE KEY TO FUTURE THERAPEUTIC APPLICATIONS IN CLINICAL PRACTICE. THIS REVIEW ELABORATES ON THE LATEST KNOWLEDGE OF EACH MECHANISM AND THE CURRENTLY AVAILABLE THERAPEUTIC AGENTS THAT TARGET EPIGENETIC MODIFICATION IN THE CONTEXT OF AKI-TO-CKD TRANSITION. FURTHER STUDIES WILL ELUCIDATE MORE DETAILED MECHANISMS AND NOVEL THERAPEUTIC TARGETS OF AKI-TO-CKD TRANSITION. 2022 5 3670 56 INFLAMMAGING AND COMPLEMENT SYSTEM: A LINK BETWEEN ACUTE KIDNEY INJURY AND CHRONIC GRAFT DAMAGE. THE ABERRANT ACTIVATION OF COMPLEMENT SYSTEM IN SEVERAL KIDNEY DISEASES SUGGESTS THAT THIS PILLAR OF INNATE IMMUNITY HAS A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF RENAL DAMAGE OF DIFFERENT ETIOLOGIES. A GROWING BODY OF EXPERIMENTAL EVIDENCE INDICATES THAT COMPLEMENT ACTIVATION CONTRIBUTES TO THE PATHOGENESIS OF ACUTE KIDNEY INJURY (AKI) SUCH AS DELAYED GRAFT FUNCTION (DGF) IN TRANSPLANT PATIENTS. AKI IS CHARACTERIZED BY THE RAPID LOSS OF THE KIDNEY'S EXCRETORY FUNCTION AND IS A COMPLEX SYNDROME CURRENTLY LACKING A SPECIFIC MEDICAL TREATMENT TO ARREST OR ATTENUATE PROGRESSION IN CHRONIC KIDNEY DISEASE (CKD). RECENT EVIDENCE SUGGESTS THAT INDEPENDENTLY FROM THE INITIAL TRIGGER (I.E., SEPSIS OR ISCHEMIA/REPERFUSIONS INJURY), AN EPISODE OF AKI IS STRONGLY ASSOCIATED WITH AN INCREASED RISK OF SUBSEQUENT CKD. THE AKI-TO-CKD TRANSITION MAY INVOLVE A WIDE RANGE OF MECHANISMS INCLUDING SCAR-FORMING MYOFIBROBLASTS GENERATED FROM DIFFERENT SOURCES, MICROVASCULAR RAREFACTION, MITOCHONDRIAL DYSFUNCTION, OR CELL CYCLE ARREST BY THE INVOLVEMENT OF EPIGENETIC, GENE, AND PROTEIN ALTERATIONS LEADING TO COMMON FINAL SIGNALING PATHWAYS [I.E., TRANSFORMING GROWTH FACTOR BETA (TGF-BETA), P16 (INK4A) , WNT/BETA-CATENIN PATHWAY] INVOLVED IN RENAL AGING. RESEARCH IN RECENT YEARS HAS REVEALED THAT SEVERAL STRESSORS OR COMPLICATIONS SUCH AS REJECTION AFTER RENAL TRANSPLANTATION CAN LEAD TO ACCELERATED RENAL AGING WITH DETRIMENTAL EFFECTS WITH THE ESTABLISHMENT OF CHRONIC PROINFLAMMATORY CELLULAR PHENOTYPES WITHIN THE KIDNEY. DESPITE A GREATER UNDERSTANDING OF THESE MECHANISMS, THE ROLE OF COMPLEMENT SYSTEM IN THE CONTEXT OF THE AKI-TO-CKD TRANSITION AND RENAL INFLAMMAGING IS STILL POORLY EXPLORED. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE RECENT FINDINGS DESCRIBING THE ROLE OF COMPLEMENT IN AKI-TO-CKD TRANSITION. WE WILL ALSO ADDRESS HOW AND WHEN COMPLEMENT INHIBITORS MIGHT BE USED TO PREVENT AKI AND CKD PROGRESSION, THEREFORE IMPROVING GRAFT FUNCTION. 2020 6 221 54 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 7 2034 40 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 8 5950 39 TARGETING THE PROGRESSION OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A DEVASTATING CONDITION THAT IS REACHING EPIDEMIC LEVELS OWING TO THE INCREASING PREVALENCE OF DIABETES MELLITUS, HYPERTENSION AND OBESITY, AS WELL AS AGEING OF THE POPULATION. REGARDLESS OF THE UNDERLYING AETIOLOGY, CKD IS SLOWLY PROGRESSIVE AND LEADS TO IRREVERSIBLE NEPHRON LOSS, END-STAGE RENAL DISEASE AND/OR PREMATURE DEATH. FACTORS THAT CONTRIBUTE TO CKD PROGRESSION INCLUDE PARENCHYMAL CELL LOSS, CHRONIC INFLAMMATION, FIBROSIS AND REDUCED REGENERATIVE CAPACITY OF THE KIDNEY. CURRENT THERAPIES HAVE LIMITED EFFECTIVENESS AND ONLY DELAY DISEASE PROGRESSION, UNDERSCORING THE NEED TO DEVELOP NOVEL THERAPEUTIC APPROACHES TO EITHER STOP OR REVERSE PROGRESSION. PRECLINICAL STUDIES HAVE IDENTIFIED SEVERAL APPROACHES THAT REDUCE FIBROSIS IN EXPERIMENTAL MODELS, INCLUDING TARGETING CYTOKINES, TRANSCRIPTION FACTORS, DEVELOPMENTAL AND SIGNALLING PATHWAYS AND EPIGENETIC MODULATORS, PARTICULARLY MICRORNAS. SOME OF THESE NEPHROPROTECTIVE STRATEGIES ARE NOW BEING TESTED IN CLINICAL TRIALS. LESSONS LEARNED FROM THE FAILURE OF CLINICAL STUDIES OF TRANSFORMING GROWTH FACTOR BETA1 (TGFBETA1) BLOCKADE UNDERSCORE THE NEED FOR ALTERNATIVE APPROACHES TO CKD THERAPY, AS STRATEGIES THAT TARGET A SINGLE PATHOGENIC PROCESS MAY RESULT IN UNEXPECTED NEGATIVE EFFECTS ON SIMULTANEOUSLY OCCURRING PROCESSES. ADDITIONAL PROMISING AVENUES INCLUDE PREVENTING TUBULAR CELL INJURY AND ANTI-FIBROTIC THERAPIES THAT TARGET ACTIVATED MYOFIBROBLASTS, THE MAIN COLLAGEN-PRODUCING CELLS. 2020 9 2788 50 FACTORS AFFECTING THE TRANSITION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: POTENTIAL MECHANISMS AND FUTURE PERSPECTIVES. ACUTE KIDNEY INJURY (AKI) IS DEFINED AS A RAPID LOSS OF KIDNEY FUNCTION CHARACTERISED BY INFLAMMATION AND CELL DEATH, ULTIMATELY LEADING TO FURTHER FUNCTIONAL AND STRUCTURAL RENAL ALTERATIONS. BASED ON EXPERIMENTAL AND EPIDEMIOLOGICAL PIECES OF EVIDENCE, AKI MAY PROGRESS TO CHRONIC KIDNEY DISEASE (CKD) EVEN AFTER A RECOVERY PERIOD DUE TO MALADAPTIVE REPAIR AND OTHER UNDERLYING MECHANISMS SUCH AS HEIGHTENED WNT SIGNALLING, OVERSTIMULATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM (RAAS) PATHWAY, EPIGENETIC ALTERATIONS AND INHIBITION OF HYPOXIA-INDUCIBLE FACTOR (HIF) DEPENDENT DEFENCES. IT HAS BEEN REPORTED THAT RAAS ACTIVATION SUBSEQUENT TO RENAL INSULT MEDIATES INFLAMMATORY AND FIBROTIC MECHANISMS, WHICH ARE A HALLMARK OF CKD. MOREOVER, INTERESTING EVIDENCE REGARDING THE EXPOSURE-DEPENDENT DUAL ROLE OF WNT SIGNALLING IN BOTH INJURY AND REPAIR, EPIGENETIC CHANGES UNDERLYING KIDNEY DISEASE SUGGEST A POTENTIAL THERAPEUTIC ROLE OF THESE PATHWAYS IN AKI TO CKD CONTINUUM. IN ADDITION, THE HYPOXIA-INDEPENDENT RENAL BENEFITS OF ERYTHROPOIETIN SUCH AS ANTI-APOPTOSIS AND TUBULAR REGENERATION ALSO PRESENT AN AUSPICIOUS TARGET WHICH COULD BE USEFUL IN CLINICAL SETTINGS. IN THIS REVIEW, THE SPECIFIC ROLES OF THESE PATHWAYS IN KIDNEY DISEASE, THEIR PATHOLOGICAL MECHANISMS AND THERAPEUTIC STRATEGIES ARE DISCUSSED. MOREOVER, NOTABLE REPORTS CONCERNING STEM CELL THERAPY WHICH HOLD PROMISE IN HALTING AKI-CKD CONTINUUM WILL BE ELABORATED. 2019 10 3466 46 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 11 2526 31 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 12 4777 34 NUTRACEUTICALS AND NETWORK PHARMACOLOGY APPROACH FOR ACUTE KIDNEY INJURY: A REVIEW FROM THE DRUG DISCOVERY ASPECT. ACUTE KIDNEY INJURY (AKI) HAS BECOME A GLOBAL HEALTH ISSUE, WITH APPROXIMATELY 12 MILLION REPORTS YEARLY, RESULTING IN A PERSISTENT INCREASE IN MORBIDITY AND MORTALITY RATES. AKI PATHOPHYSIOLOGY IS MULTIFACTORIAL INVOLVING OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC MODIFICATIONS, INFLAMMATION, AND EVENTUALLY, CELL DEATH. HENCE, THERAPIES ABLE TO TARGET MULTIPLE PATHOMECHANISMS CAN AID IN AKI MANAGEMENT. TO CHANGE THE DRUG DISCOVERY FRAMEWORK FROM "ONE DRUG, ONE TARGET" TO "MULTICOMPONENT, MULTITARGET," NETWORK PHARMACOLOGY IS EVOLVING AS A NEXT-GENERATION RESEARCH APPROACH. RESEARCHERS HAVE USED THE NETWORK PHARMACOLOGY APPROACH TO PREDICT THE ROLE OF NUTRACEUTICALS AGAINST DIFFERENT AILMENTS INCLUDING AKI. NUTRACEUTICALS (HERBAL PRODUCTS, ISOLATED NUTRIENTS, AND DIETARY SUPPLEMENTS) BELONG TO THE PIONEERING CATEGORY OF NATURAL PRODUCTS AND HAVE SHOWN PROTECTIVE ACTION AGAINST AKI. NUTRACEUTICALS HAVE RECENTLY DRAWN ATTENTION BECAUSE OF THEIR ABILITY TO PROVIDE PHYSIOLOGICAL BENEFITS WITH LESS TOXIC EFFECTS. THIS REVIEW EMPHASIZES THE NUTRACEUTICALS THAT EXHIBITED RENOPROTECTION AGAINST AKI AND CAN BE USED EITHER AS MONOTHERAPY OR ADJUVANT WITH CONVENTIONAL THERAPIES TO BOOST THEIR EFFECTIVENESS AND LESSEN THE ADVERSE EFFECTS. ADDITIONALLY, THE STUDY SHEDS LIGHT ON THE APPLICATION OF NETWORK PHARMACOLOGY AS A COST-EFFECTIVE AND TIME-SAVING APPROACH FOR THE THERAPEUTIC TARGET PREDICTION OF NUTRACEUTICALS AGAINST AKI. 2023 13 5025 23 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 14 6051 41 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 15 3035 33 GENETICS/GENOMICS IN CHRONIC KIDNEY DISEASE--TOWARDS PERSONALIZED MEDICINE? THE PROGRESSION RATE OF CHRONIC KIDNEY DISEASE (CKD) TO ITS TERMINAL STAGE, END-STAGE RENAL DISEASE (ESRD), AND THE DEVELOPMENT AND SEVERITY OF VARIOUS COMPLICATIONS, ARE AT LEAST INDIRECTLY INFLUENCED BY GENETIC--AND EPIGENETIC--FACTORS. FOR YEARS, SCIENTISTS HAVE HELD OUT HOPE THAT THE RAPIDLY EVOLVING FIELD OF GENETICS COULD TRANSFORM MEDICAL DIAGNOSIS AND TREATMENT, MOVING BEYOND A TRIAL-AND-ERROR APPROACH TOWARDS "PERSONALIZED MEDICINE." INDEED, THERE ARE NOW SIGNS THAT THE ROLE OF GENETICS AND THE PURSUIT OF "PERSONALIZED MEDICINE" IN MEDICAL CARE WILL BE A PRIORITY FOR GOVERNMENTS DURING YEARS TO COME. BUT THE VISION OF INDIVIDUALIZED TREATMENT BASED ON A PATIENT'S GENETIC MAKEUP AND OTHER BIOLOGICAL MARKERS HAS YET TO MATERIALIZE IN THE FIELD OF CKD AND ESRD. AS THE TOXIC UREMIC ENVIRONMENT MAY RENDER CKD PATIENTS MORE SENSITIVE TO THE EFFECTS OF GENETIC VARIANTS, IT IS LIKELY THAT GENETIC FACTORS COULD BE OF SPECIAL IMPORTANCE IN THIS HIGH-RISK POPULATION. THEREFORE, OUTCOME IN THE CKD POPULATION MAY BE IMPROVED BY ESTABLISHING INDIVIDUAL GENETIC/EPIGENETIC PROFILES, THUS ENABLING PHYSICIANS TO DESIGN AN INDIVIDUALIZED THERAPEUTIC STRATEGY. PERSONALIZED MEDICINE BASED ON A MORE INDIVIDUALIZED THERAPY COULD BE APPLIED IN, FOR EXAMPLE, PHARMACOTHERAPY (CYP GENES), DIALYSIS THERAPY, AND NUTRITIONAL AND LIFESTYLE MODIFICATIONS. 2009 16 220 52 ACUTE KIDNEY DISEASE: AN OVERVIEW OF THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT. ACUTE KIDNEY INJURY (AKI) INCREASES THE RISK OF CHRONIC KIDNEY DISEASE (CKD), AND AKI AND CKD ARE SEEN AS INTERCONNECTED SYNDROMES. ACUTE KIDNEY DISEASE (AKD) IS DEFINED AS SUBACUTE DAMAGE AND/OR LOSS OF KIDNEY FUNCTION OCCURRING 7 TO 90 DAYS AFTER AKI, DURING WHICH PERIOD KEY INTERVENTIONS MAY BE INITIATED TO HINDER THE DEVELOPMENT OF CKD. WHILE AKD IS USUALLY UNDER-RECOGNIZED, IT IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY GLOBALLY. THIS REVIEW ARTICLE AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE CONCERNING THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT OF AKD WITH THE AIM TO DEVELOP MONITORING STRATEGIES AND THERAPEUTIC AGENTS OF AKD. GENERALLY, AKD TENDS TO OCCUR MORE FREQUENTLY IN THE ELDERLY AND THOSE WITH CHRONIC DISEASES, SUCH AS HYPERTENSION, DIABETES MELLITUS, AND METABOLIC SYNDROME. IN ADDITION, THE SEVERITY, DURATION, AND FREQUENCY OF AKI ARE INDEPENDENT RISK FACTORS FOR AKD. INVESTIGATIONS OF SEVERAL MECHANISMS OF AKD, SUCH AS RENAL TUBULAR EPITHELIUM CELL-CYCLE ARREST, EPIGENETIC CHANGE, CHRONIC INFLAMMATION, MITOCHONDRIA DYSFUNCTION, FAILED REGENERATION OF TUBULAR CELLS, METABOLIC REPROGRAMMING, AND RENIN-ANGIOTENSIN SYSTEM (RAS) ACTIVATION, HAVE IDENTIFIED ADDITIONAL POTENTIAL PHARMACOTHERAPY TARGETS. MANAGEMENT OF AKD INCLUDES PREVENTION OF REPEATED AKI, EARLY AND REGULAR FOLLOW-UP BY A NEPHROLOGIST, RESUMPTION AND ADJUSTMENT OF ESSENTIAL MEDICATION, OPTIMIZATION OF BLOOD PRESSURE CONTROL AND NUTRITION MANAGEMENT, AND DEVELOPMENT OF NEW PHARMACEUTICAL AGENTS INCLUDING RAS INHIBITORS. FINALLY, WE OUTLINE A CARE BUNDLE FOR AKD PATIENTS BASED ON IMPORTANT LESSONS LEARNED FROM STUDIES AND REGISTRIES AND IDENTIFY THE NEED FOR CLINICAL TRIALS OF RAS INHIBITORS OR OTHER NOVEL AGENTS TO IMPEDE ENSUING CKD DEVELOPMENT. 2023 17 6446 46 THERAPEUTIC INSIGHTS IN CHRONIC KIDNEY DISEASE PROGRESSION. CHRONIC KIDNEY DISEASE (CKD) HAS BEEN RECOGNIZED AS A LEADING PUBLIC HEALTH PROBLEM WORLDWIDE. THROUGH ITS EFFECT ON CARDIOVASCULAR RISK AND END-STAGE KIDNEY DISEASE, CKD DIRECTLY AFFECTS THE GLOBAL BURDEN OF MORBIDITY AND MORTALITY. CLASSICAL OPTIMAL MANAGEMENT OF CKD INCLUDES BLOOD PRESSURE CONTROL, TREATMENT OF ALBUMINURIA WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR ANGIOTENSIN II RECEPTOR BLOCKERS, AVOIDANCE OF POTENTIAL NEPHROTOXINS AND OBESITY, DRUG DOSING ADJUSTMENTS, AND CARDIOVASCULAR RISK REDUCTION. DIABETES MIGHT ACCOUNT FOR MORE THAN HALF OF CKD BURDEN, AND OBESITY IS THE MOST IMPORTANT PROMPTED FACTOR FOR THIS DISEASE. NEW ANTIHYPERGLYCEMIC DRUGS, SUCH AS SODIUM-GLUCOSE-COTRANSPORTER 2 INHIBITORS HAVE SHOWN TO SLOW THE DECLINE OF GFR, BRINGING ADDITIONAL BENEFIT IN WEIGHT REDUCTION, CARDIOVASCULAR, AND OTHER KIDNEY OUTCOMES. ON THE OTHER HAND, A NEW GENERATION OF NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST HAS RECENTLY BEEN DEVELOPED TO OBTAIN A SELECTIVE RECEPTOR INHIBITION REDUCING SIDE EFFECTS LIKE HYPERKALEMIA AND THEREBY MAKING THE DRUGS SUITABLE FOR ADMINISTRATION TO CKD PATIENTS. MOREOVER, TWO NEW POTASSIUM-LOWERING THERAPIES HAVE SHOWN TO IMPROVE TOLERANCE, ALLOWING FOR HIGHER DOSAGE OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND THEREFORE ENHANCING THEIR NEPHROPROTECTIVE EFFECT. REGARDLESS OF ITS CAUSE, CKD IS CHARACTERIZED BY REDUCED RENAL REGENERATION CAPACITY, MICROVASCULAR DAMAGE, OXIDATIVE STRESS AND INFLAMMATION, RESULTING IN FIBROSIS AND PROGRESSIVE, AND IRREVERSIBLE NEPHRON LOSS. THEREFORE, A HOLISTIC APPROACH SHOULD BE TAKEN TARGETING THE DIVERSE PROCESSES AND BIOLOGICAL CONTEXTS THAT ARE ASSOCIATED WITH CKD PROGRESSION. TO DATE, THERAPEUTIC INTERVENTIONS WHEN TUBULOINTERSTITIAL FIBROSIS IS ALREADY ESTABLISHED HAVE PROVED TO BE INSUFFICIENT, THUS RESEARCH EFFORT SHOULD FOCUS ON UNRAVELING EARLY DISEASE MECHANISMS. AN ARRAY OF NOVEL THERAPEUTIC APPROACHES TARGETING EPIGENETIC REGULATORS ARE NOW UNDERGOING PHASE II OR PHASE III TRIALS AND MIGHT PROVIDE A SIMULTANEOUS REGULATORY ACTIVITY THAT COORDINATELY REGULATE DIFFERENT ASPECTS OF CKD PROGRESSION. 2021 18 1977 33 EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY. ACUTE KIDNEY INJURY (AKI) IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE AND DEATH. DESPITE PROGRESS MADE IN UNDERSTANDING THE CELLULAR AND MOLECULAR BASIS OF AKI PATHOGENESIS THERE HAS BEEN NO IMPROVEMENT IN THE HIGH MORTALITY RATE FROM THIS DISEASE IN DECADES. EPIGENETICS IS ONE OF THE MOST INTENSIVELY STUDIED FIELDS OF BIOLOGY TODAY AND REPRESENTS A NEW PARADIGM FOR UNDERSTANDING THE PATHOPHYSIOLOGY OF DISEASE. ALTHOUGH EPIGENETICS OF AKI IS A NASCENT FIELD, THE AVAILABLE INFORMATION ALREADY IS PROVIDING COMPELLING EVIDENCE THAT CHROMATIN BIOLOGY PLAYS A CRITICAL ROLE IN THIS DISEASE. IN THIS ARTICLE WE EXPLORE WHAT IS KNOWN ABOUT THE CONTRIBUTION OF EPIGENETIC MECHANISMS TO THE PATHOPHYSIOLOGY OF AKI AND HOW THIS KNOWLEDGE ALREADY IS GUIDING THE DEVELOPMENT OF NEW DIAGNOSTIC TOOLS AND EPIGENETIC THERAPIES. 2013 19 6299 52 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 2193 49 EPIGENETIC MODIFICATION DRIVES ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) IS A COMMON CLINICAL CRITICAL DISEASE. DUE TO ITS HIGH MORBIDITY, INCREASING RISK OF COMPLICATIONS, HIGH MORTALITY RATE, AND HIGH MEDICAL COSTS, IT HAS BECOME A GLOBAL CONCERN FOR HUMAN HEALTH PROBLEMS. INITIALLY, RESEARCHERS BELIEVED THAT KIDNEYS HAVE A STRONG ABILITY TO REGENERATE AND REPAIR, BUT STUDIES OVER THE PAST 20 YEARS HAVE FOUND THAT KIDNEYS DAMAGED BY AKI ARE OFTEN INCOMPLETE OR EVEN UNABLE TO REPAIR. EVEN WHEN SERUM CREATININE RETURNS TO BASELINE LEVELS, RENAL STRUCTURAL DAMAGE PERSISTS FOR A LONG TIME, LEADING TO THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE MECHANISM OF AKI-TO-CKD TRANSITION HAS NOT BEEN FULLY ELUCIDATED. AS AN IMPORTANT REGULATOR OF GENE EXPRESSION, EPIGENETIC MODIFICATIONS, SUCH AS HISTONE MODIFICATION, DNA METHYLATION, AND NONCODING RNAS, MAY PLAY AN IMPORTANT ROLE IN THIS PROCESS. ALTERATIONS IN EPIGENETIC MODIFICATION ARE INDUCED BY HYPOXIA, THUS PROMOTING THE EXPRESSION OF INFLAMMATORY FACTOR-RELATED GENES AND COLLAGEN SECRETION. THIS REVIEW ELABORATED THE ROLE OF EPIGENETIC MODIFICATIONS IN AKI-TO-CKD PROGRESSION, THE DIAGNOSTIC VALUE OF EPIGENETIC MODIFICATIONS BIOMARKERS IN AKI CHRONIC OUTCOME, AND THE POTENTIAL ROLE OF TARGETING EPIGENETIC MODIFICATIONS IN THE PREVENTION AND TREATMENT OF AKI TO CKD, IN ORDER TO PROVIDE IDEAS FOR THE SUBSEQUENT ESTABLISHMENT OF TARGETED THERAPEUTIC STRATEGIES TO PREVENT THE PROGRESSION OF RENAL TUBULAR-INTERSTITIAL FIBROSIS. 2021