1 5370 74 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 2 6299 30 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 3 2579 19 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 4 2195 27 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 5 5950 33 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 6 5660 24 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 7 221 31 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 8 5258 22 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 9 5988 24 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 10 2193 26 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 11 3885 35 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 12 6638 28 UNRAVELING THE EPIGENETIC LANDSCAPE OF GLOMERULAR CELLS IN KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A MAJOR PUBLIC HEALTH CONCERN AND ITS PREVALENCE AND INCIDENCE ARE RISING QUICKLY. IT IS A NON-COMMUNICABLE DISEASE PRIMARILY CAUSED BY DIABETES AND/OR HYPERTENSION AND IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. DESPITE DECADES OF RESEARCH EFFORTS, THE PATHOGENESIS OF CKD REMAINS A PUZZLE WITH MISSING PIECES. UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS THAT GOVERN THE LOSS OF KIDNEY FUNCTION IS CRUCIAL. ABRUPT REGULATION OF GENE EXPRESSION IN KIDNEY CELLS IS APPARENT IN CKD AND SHOWN TO BE RESPONSIBLE FOR DISEASE ONSET AND PROGRESSION. GENE EXPRESSION REGULATION EXTENDS BEYOND DNA SEQUENCE AND INVOLVES EPIGENETIC MECHANISMS INCLUDING CHANGES IN DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, DRIVEN BY THE ACTIVITY OF SPECIFIC ENZYMES. RECENT ADVANCES DEMONSTRATE THE ESSENTIAL PARTICIPATION OF EPIGENETICS IN KIDNEY (PATHO)PHYSIOLOGY, AS ITS ACTIONS REGULATE BOTH THE INTEGRITY OF CELLS BUT ALSO TRIGGERS DELETERIOUS SIGNALING PATHWAYS. HERE, WE REVIEW THE KNOWN EPIGENETIC PROCESSES REGULATING THE COMPLEX FILTRATION UNIT OF THE KIDNEY, THE GLOMERULI. THE REVIEW WILL ELABORATE ON NOVEL INSIGHTS INTO HOW EPIGENETICS CONTRIBUTES TO CELL INJURY IN THE CKD SETTING MAJORLY FOCUSING ON KIDNEY GLOMERULAR CELLS: THE GLOMERULAR ENDOTHELIAL CELLS, THE MESANGIAL CELLS, AND THE SPECIALIZED AND TERMINALLY DIFFERENTIATED PODOCYTE CELLS. 2021 13 1880 27 EMERGING STRATEGIES TO DISRUPT THE CENTRAL TGF-BETA AXIS IN KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE (CKD) AFFECTS MORE THAN 20 MILLION PEOPLE IN THE UNITED STATES AND THE GLOBAL BURDEN OF THIS DISORDER IS INCREASING. MANY AFFECTED INDIVIDUALS WILL PROGRESS TO END STAGE KIDNEY DISEASE NECESSITATING DIALYSIS OR TRANSPLANTATION. CKD IS ALSO A MAJOR INDEPENDENT CONTRIBUTOR TO THE RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. TUBULOINTERSTITIAL FIBROSIS IS A FINAL COMMON PATHWAY FOR MOST CAUSES OF PROGRESSIVE CKD. CURRENTLY, THERE ARE NO CLINICALLY AVAILABLE THERAPIES TARGETING FIBROSIS THAT CAN SLOW THE DECLINE IN KIDNEY FUNCTION. ALTHOUGH IT HAS LONG BEEN KNOWN THAT TGF-BETA SIGNALING IS A CRITICAL MEDIATOR OF KIDNEY FIBROSIS, TRANSLATING THIS KNOWLEDGE TO THE CLINIC HAS BEEN CHALLENGING. IN THIS REVIEW, WE HIGHLIGHT SOME RECENT INSIGHTS INTO THE MECHANISMS OF TGF-BETA SIGNALING THAT TARGET ACTIVATION OF THIS CYTOKINE AT THE SITE OF INJURY OR SELECTIVELY INHIBIT PRO-FIBROTIC GENE EXPRESSION. MOLECULES DIRECTED AT THESE TARGETS HOLD THE PROMISE OF ATTAINING THERAPEUTIC EFFICACY WHILE LIMITING TOXICITY SEEN WITH GLOBAL INHIBITION OF TGF-BETA. KIDNEY INJURY HAS PROFOUND EPIGENETIC EFFECTS LEADING TO ALTERED EXPRESSION OF MORE THAN A THOUSAND GENES. WE DISCUSS HOW DRUGS TARGETING EPIGENETIC MODIFICATIONS, SOME OF WHICH ARE IN USE FOR CANCER THERAPY, HAVE THE POTENTIAL TO REPROGRAM GENE REGULATORY NETWORKS TO FAVOR ADAPTIVE REPAIR AND PREVENT FIBROSIS. THE LACK OF RELIABLE BIOMARKERS OF KIDNEY FIBROSIS IS A MAJOR LIMITATION IN DESIGNING CLINICAL TRIALS FOR TESTING CKD TREATMENTS. WE CONCLUDE BY REVIEWING RECENT ADVANCES IN FIBROSIS BIOMARKER DEVELOPMENT. 2019 14 2293 26 EPIGENETIC REGULATION IN THE ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. EPIGENETIC MODIFICATIONS HAVE EMERGED AS A NEW, IMPORTANT CONTRIBUTOR TO GENE EXPRESSION REGULATION IN BOTH NORMAL AND PATHOPHYSIOLOGICAL CONDITIONS. EPIGENETICS HAVE BEEN STUDIED IN MANY DISEASES AND CONDITIONS SUCH AS ACUTE KIDNEY INJURY (AKI), A SYNDROME WITH A HIGH PREVALENCE THAT CARRIES A POOR PROGNOSIS WITH INCREASED MORBIDITY AND MORTALITY. IN ADDITION, IT HAS RECENTLY BEEN SHOWN THAT AKI INCREASES THE RISK FOR THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE SPECIFIC MOLECULAR MECHANISMS BY WHICH AKI INCREASES THE RISK OF CKD AND END STAGE RENAL DISEASE (ESRD) REMAIN UNKNOWN, ALTHOUGH THERE IS NEW EVIDENCE SUPPORTING A ROLE OF EPIGENETIC CHANGES. THE MOST STUDIED EPIGENETIC REGULATIONS IN AKI ARE CHROMATIN COMPACTION, DNA METHYLATION, AND HISTONE ACETYLATION/DEACETYLATION. THESE MODIFICATIONS PREDOMINANTLY INCREASE THE PRODUCTION OF PRO-INFLAMMATORY AND PROFIBROTIC CYTOKINES SUCH AS: MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), COMPLEMENT PROTEIN 3 (C3), TRANSFORMING GROWTH FACTOR BETA (TGF-BETA) THAT HAVE BEEN SHOWN FOR PERPETUATING INFLAMMATION, PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ULTIMATELY CAUSING RENAL FIBROSIS. A REVIEW OF EPIGENETIC MECHANISMS, THE PATHOPHYSIOLOGY OF AKI AND RECENT STUDIES THAT IMPLICATE EPIGENETIC MODIFICATIONS IN AKI AND IN THE TRANSITION TO CKD ARE DISCUSSED BELOW. 2015 15 4381 30 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 16 6451 30 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 17 2286 23 EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION. KIDNEY TRANSPLANTATION IS A STANDARD CARE FOR END STAGE RENAL DISEASE, BUT IT IS ALSO ASSOCIATED WITH A COMPLEX PATHOGENESIS INCLUDING ISCHEMIA-REPERFUSION INJURY, INFLAMMATION, AND DEVELOPMENT OF FIBROSIS. OVER THE PAST DECADE, ACCUMULATING EVIDENCE HAS SUGGESTED A ROLE OF EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION, INVOLVING DNA METHYLATION, HISTONE MODIFICATION, AND VARIOUS KINDS OF NON-CODING RNAS. HERE, WE ANALYZE THESE RECENT STUDIES SUPPORTING THE ROLE OF EPIGENETIC REGULATION IN DIFFERENT PATHOLOGICAL PROCESSES OF KIDNEY TRANSPLANTATION, I.E., ISCHEMIA-REPERFUSION INJURY, ACUTE REJECTION, AND CHRONIC GRAFT PATHOLOGIES INCLUDING RENAL INTERSTITIAL FIBROSIS. FURTHER INVESTIGATION OF EPIGENETIC ALTERATIONS, THEIR PATHOLOGICAL ROLES AND UNDERLYING MECHANISMS IN KIDNEY TRANSPLANTATION MAY LEAD TO NEW STRATEGIES FOR THE DISCOVERY OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2022 18 4668 27 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 19 1170 35 CONTRIBUTION OF GENETICS AND EPIGENETICS TO PROGRESSION OF KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE (CKD) WHICH CAN LEAD TO END-STAGE RENAL FAILURE REMAINS A PRINCIPAL CHALLENGE IN NEPHROLOGY. WHILE MECHANISTIC STUDIES PROVIDED EXTENSIVE INSIGHTS INTO THE COMMON PATHWAYS OF FIBROGENESIS WHICH UNDERLIE THE PROGRESSION OF CKD, THESE PRE-CLINICAL STUDIES FAIL TO FULLY EXPLAIN THE VASTLY DIFFERENT PROGRESSION SLOPES OF INDIVIDUAL PATIENTS. RECENT STUDIES PROVIDE EVIDENCE THAT GENETIC POLYMORPHISMS AND EPIGENETIC VARIATIONS DETERMINE THE INDIVIDUAL SUSCEPTIBILITY OF PATIENTS TO DEVELOP CHRONIC PROGRESSIVE KIDNEY DISEASE. HERE, WE REVIEW RECENT INSIGHTS THAT WERE PROVIDED BY GENOME-WIDE ASSOCIATION STUDIES (GWASS), GENE-LINKAGE STUDIES AND EPIGENOME ANALYSIS. THE PROGRESSION OF CKD TOWARDS END-STAGE RENAL FAILURE REMAINS A PRINCIPAL UNSOLVED PROBLEM IN NEPHROLOGY AS EFFECTIVE THERAPIES AND PREDICTIVE TESTS ARE STILL NOT AVAILABLE [ 1, 2]. CHRONIC PROGRESSIVE KIDNEY DISEASE IS CAUSED BY A WIDE RANGE OF DISEASES, WITH DIABETES MELLITUS, HYPERTENSION AND PRIMARY GLOMERULOPATHIES BEING THE MOST COMMON CAUSES IN THE WESTERN WORLD [ 3]. INFECTIONS, PHYSICAL OBSTRUCTION, INTERSTITIAL NEPHRITIDES AND GENETIC CYSTIC KIDNEY DISEASES ARE ALSO COMMON CAUSES OF END-STAGE RENAL DISEASE (ESRD) [ 3]. REGARDLESS OF THE PRIMARY UNDERLYING DISEASE, CHRONICALLY INJURED KIDNEYS ARE HISTOMORPHOLOGICALLY CHARACTERIZED BY TUBULOINTERSTITIAL FIBROSIS [ 1]. IN FACT, THE EXTENT OF TUBULOINTERSTITIAL FIBROSIS IS THE BEST PREDICTOR FOR KIDNEY SURVIVAL, IRRESPECTIVE OF THE UNDERLYING DISEASE. FOR THIS REASON, FIBROSIS IS CONSIDERED THE COMMON PATHWAY OF CHRONIC PROGRESSIVE KIDNEY DISEASE [ 1]. FIBROGENESIS IS A PATHOLOGICAL SCARRING PROCESS WHICH INVOLVES ACCUMULATION OF ACTIVATED FIBROBLASTS, EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX, FAILED REGENERATION OF TUBULAR EPITHELIUM, MICROVASCULAR RAREFACTION AND (MOSTLY STERILE) INFLAMMATION [ 4]. FIBROGENESIS DEPENDS ON A COMPLEX INTERACTION OF THE INVOLVED CELL TYPES WHICH IS ORCHESTRATED BY AN EXTENSIVE NETWORK OF GROWTH FACTORS AND SIGNALLING PATHWAYS (WHICH ARE REVIEWED EXTENSIVELY ELSEWHERE) [ 1]. IN VIEW OF THE DETAILED MECHANISTIC KNOWLEDGE OF THE PATHWAYS THAT ORCHESTRATE RENAL FIBROGENESIS, IT IS PUZZLING WHY PROGRESSION RATES OF CKD DIFFER DRAMATICALLY AMONG PATIENTS WITH IDENTICAL UNDERLYING DISEASES [ 1, 2]. THE FIBROTIC PATHWAYS ARE KNOWN, BUT THE SWITCHES THAT CONTROL THEIR INTENSITIES AND WHICH DETERMINE THE SPEED AT WHICH FIBROSIS MOVES ALONG THE PROGRESSION SLOPE ARE NOT YET UNDERSTOOD [ 1, 2]. THE CONCEPT THAT GENETIC POLYMORPHISMS ARE THE BASIS FOR INDIVIDUAL PROGRESSION RATES OF CKD IS AN OBVIOUS AND ATTRACTIVE ONE. DISTINCT SUSCEPTIBILITIES OF DIFFERENT MOUSE AND RAT STRAINS TO EXPERIMENTAL CKD ARE A STRONG TESTAMENT OF THE IMPACT OF GENETIC VARIATIONS ON RENAL FIBROGENESIS. IDENTIFICATION OF THE UNDERLYING GENETIC POLYMORPHISMS AND MECHANISTIC PROOF OF THEIR INVOLVEMENT IN THE PROGRESSION OF CKD, HOWEVER, IS AN ONGOING CHALLENGE. THERE ARE TWO BASIC APPROACHES: ONE STRATEGY IS TO PERFORM UNBIASED SCREENING TO IDENTIFY GENES WHICH ARE ASSOCIATED WITH CHRONIC PROGRESSIVE KIDNEY DISEASE AND TO THEN PROVE THEIR MECHANISTIC RELEVANCE IN EXPERIMENTAL STUDIES ('GENOTYPE TO PHENOTYPE APPROACH'). THE SECOND STRATEGY IS TO SELECTIVELY ANALYSE POLYMORPHISMS OF GENES WHICH HAVE BEEN IDENTIFIED IN MECHANISTIC STUDIES AS DRIVERS OF RENAL FIBROGENESIS WITH REGARD TO THEIR ASSOCIATION WITH CKD (PHENOTYPE TO GENOTYPE APPROACH). THE PUZZLING OBSERVATION, HOWEVER, IS THAT GENETIC ANALYSIS AND MECHANISTIC STUDIES SO FAR RARELY COMPLEMENT EACH OTHER. THE CURRENT STATE OF AFFAIRS IS REVIEWED IN MORE DETAIL BELOW. 2014 20 6409 19 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