1 699 120 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 2 6910 21 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 3 5993 27 TGFBETA PROMOTES FIBROSIS BY MYST1-DEPENDENT EPIGENETIC REGULATION OF AUTOPHAGY. ACTIVATION OF FIBROBLASTS IS ESSENTIAL FOR PHYSIOLOGICAL TISSUE REPAIR. UNCONTROLLED ACTIVATION OF FIBROBLASTS, HOWEVER, MAY LEAD TO TISSUE FIBROSIS WITH ORGAN DYSFUNCTION. ALTHOUGH SEVERAL PATHWAYS CAPABLE OF PROMOTING FIBROBLAST ACTIVATION AND TISSUE REPAIR HAVE BEEN IDENTIFIED, THEIR INTERPLAY IN THE CONTEXT OF CHRONIC FIBROTIC DISEASES REMAINS INCOMPLETELY UNDERSTOOD. HERE, WE PROVIDE EVIDENCE THAT TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) ACTIVATES AUTOPHAGY BY AN EPIGENETIC MECHANISM TO AMPLIFY ITS PROFIBROTIC EFFECTS. TGFBETA INDUCES AUTOPHAGY IN FIBROTIC DISEASES BY SMAD3-DEPENDENT DOWNREGULATION OF THE H4K16 HISTONE ACETYLTRANSFERASE MYST1, WHICH REGULATES THE EXPRESSION OF CORE COMPONENTS OF THE AUTOPHAGY MACHINERY SUCH AS ATG7 AND BECLIN1. ACTIVATION OF AUTOPHAGY IN FIBROBLASTS PROMOTES COLLAGEN RELEASE AND IS BOTH, SUFFICIENT AND REQUIRED, TO INDUCE TISSUE FIBROSIS. FORCED EXPRESSION OF MYST1 ABROGATES THE STIMULATORY EFFECTS OF TGFBETA ON AUTOPHAGY AND RE-ESTABLISHES THE EPIGENETIC CONTROL OF AUTOPHAGY IN FIBROTIC CONDITIONS. INTERFERENCE WITH THE ABERRANT ACTIVATION OF AUTOPHAGY INHIBITS TGFBETA-INDUCED FIBROBLAST ACTIVATION AND AMELIORATES EXPERIMENTAL DERMAL AND PULMONARY FIBROSIS. THESE FINDINGS LINK UNCONTROLLED TGFBETA SIGNALING TO ABERRANT AUTOPHAGY AND DEREGULATED EPIGENETICS IN FIBROTIC DISEASES AND MAY CONTRIBUTE TO THE DEVELOPMENT OF THERAPEUTIC INTERVENTIONS IN FIBROTIC DISEASES. 2021 4 3512 22 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 5 3931 24 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 6 5994 34 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 7 692 46 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 8 4661 19 NEW ASPECTS OF THE EPIGENETIC REGULATION OF EMT RELATED TO PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE FIBROTIC DISEASE THAT RESULTS IN IMPAIRED GAS EXCHANGE, VENTILATION, AND EVENTUAL DEATH. THE PRO-FIBROTIC ENVIRONMENT IS INSTIGATED BY VARIOUS FACTORS, LEADING TO THE TRANSFORMATION OF EPITHELIAL CELLS INTO MYOFIBROBLASTS AND/OR FIBROBLASTS THAT TRIGGER FIBROSIS. EPITHELIAL MESENCHYMAL TRANSITION (EMT) IS A BIOLOGICAL PROCESS THAT PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PULMONARY FIBROSIS. EPIGENETIC REGULATION OF TISSUE-STROMAL CROSSTALK INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA, AND CHROMATIN REMODELING PLAYS A KEY ROLE IN THE CONTROL OF EMT. THE REVIEW INVESTIGATES THE EPIGENETIC REGULATION OF EMT AND ITS SIGNIFICANCE IN PULMONARY FIBROSIS. 2023 9 3674 22 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 10 5992 30 TGF-BETA: THE MASTER REGULATOR OF FIBROSIS. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS THE PRIMARY FACTOR THAT DRIVES FIBROSIS IN MOST, IF NOT ALL, FORMS OF CHRONIC KIDNEY DISEASE (CKD). INHIBITION OF THE TGF-BETA ISOFORM, TGF-BETA1, OR ITS DOWNSTREAM SIGNALLING PATHWAYS SUBSTANTIALLY LIMITS RENAL FIBROSIS IN A WIDE RANGE OF DISEASE MODELS WHEREAS OVEREXPRESSION OF TGF-BETA1 INDUCES RENAL FIBROSIS. TGF-BETA1 CAN INDUCE RENAL FIBROSIS VIA ACTIVATION OF BOTH CANONICAL (SMAD-BASED) AND NON-CANONICAL (NON-SMAD-BASED) SIGNALLING PATHWAYS, WHICH RESULT IN ACTIVATION OF MYOFIBROBLASTS, EXCESSIVE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) AND INHIBITION OF ECM DEGRADATION. THE ROLE OF SMAD PROTEINS IN THE REGULATION OF FIBROSIS IS COMPLEX, WITH COMPETING PROFIBROTIC AND ANTIFIBROTIC ACTIONS (INCLUDING IN THE REGULATION OF MESENCHYMAL TRANSITIONING), AND WITH COMPLEX INTERPLAY BETWEEN TGF-BETA/SMADS AND OTHER SIGNALLING PATHWAYS. STUDIES OVER THE PAST 5 YEARS HAVE IDENTIFIED ADDITIONAL MECHANISMS THAT REGULATE THE ACTION OF TGF-BETA1/SMAD SIGNALLING IN FIBROSIS, INCLUDING SHORT AND LONG NONCODING RNA MOLECULES AND EPIGENETIC MODIFICATIONS OF DNA AND HISTONE PROTEINS. ALTHOUGH DIRECT TARGETING OF TGF-BETA1 IS UNLIKELY TO YIELD A VIABLE ANTIFIBROTIC THERAPY DUE TO THE INVOLVEMENT OF TGF-BETA1 IN OTHER PROCESSES, GREATER UNDERSTANDING OF THE VARIOUS PATHWAYS BY WHICH TGF-BETA1 CONTROLS FIBROSIS HAS IDENTIFIED ALTERNATIVE TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS TO HALT THIS MOST DAMAGING PROCESS IN CKD. 2016 11 5733 22 SMALL MOLECULES AGAINST THE ORIGIN AND ACTIVATION OF MYOFIBROBLAST FOR RENAL INTERSTITIAL FIBROSIS THERAPY. RENAL INTERSTITIAL FIBROSIS (RIF) IS A COMMON PATHOLOGICAL RESPONSE IN A BROAD RANGE OF PREVALENT CHRONIC KIDNEY DISEASES AND ULTIMATELY LEADS TO RENAL FAILURE AND DEATH. ALTHOUGH RIF CAUSES A HIGH MORBI-MORTALITY WORLDWIDE, EFFECTIVE THERAPEUTIC DRUGS ARE URGENTLY NEEDED. MYOFIBROBLASTS ARE IDENTIFIED AS THE MAIN EFFECTOR DURING THE PROCESS OF RIF. MULTIPLE TYPES OF CELLS, INCLUDING FIBROBLASTS, EPITHELIAL CELLS, ENDOTHELIAL CELLS, MACROPHAGES AND PERICYTES, CONTRIBUTE TO RENAL MYOFIBROBLASTS ORIGIN, AND LOTS OF MEDIATORS, INCLUDING SIGNALING PATHWAYS (TRANSFORMING GROWTH FACTOR-BETA1, MAMMALIAN TARGET OF RAPAMYCIN AND REACTIVE OXYGEN SPECIES) AND EPIGENETIC MODIFICATIONS (HISTONE ACETYLATION, MICRORNA AND LONG NON-CODING RNA) ARE PARTICIPATED IN RENAL MYOFIBROBLASTS ACTIVATION DURING RENAL FIBROGENESIS, SUGGESTING THAT THESE MEDIATORS MAY BE THE PROMISING TARGETS FOR TREATING RIF. IN ADDITION, MANY SMALL MOLECULES SHOW PROFOUND THERAPEUTIC EFFECTS ON RIF BY SUPPRESSING THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS. TAKEN TOGETHER, THE REVIEW FOCUSES ON THE MECHANISMS OF THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS IN RIF AND THE SMALL MOLECULES AGAINST THEM IMPROVING RIF, WHICH WILL PROVIDE A NEW INSIGHT FOR RIF THERAPY. 2021 12 1764 68 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS. 2022 13 4358 25 MIR-338-3P BLOCKS TGFBETA-INDUCED MYOFIBROBLAST DIFFERENTIATION THROUGH THE INDUCTION OF PTEN. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC INTERSTITIAL LUNG DISEASE. THE PATHOGENESIS OF IPF IS NOT COMPLETELY UNDERSTOOD. HOWEVER, NUMEROUS GENES ARE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF PULMONARY FIBROSIS, INDICATING THERE IS A SIGNIFICANT GENETIC COMPONENT TO THE PATHOGENESIS OF IPF. EPIGENETIC INFLUENCES ON THE DEVELOPMENT OF HUMAN DISEASE, INCLUDING PULMONARY FIBROSIS, REMAIN TO BE FULLY ELUCIDATED. IN THIS PAPER, WE IDENTIFY MIR-338-3P AS A MICRORNA SEVERELY DOWNREGULATED IN THE LUNGS OF PATIENTS WITH PULMONARY FIBROSIS AND IN EXPERIMENTAL MODELS OF PULMONARY FIBROSIS. TREATMENT OF PRIMARY HUMAN LUNG FIBROBLASTS WITH MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION AND MATRIX PROTEIN PRODUCTION. PUBLISHED AND PROPOSED TARGETS OF MIR-338-3P SUCH AS TGFBETA RECEPTOR 1, MEK/ERK 1/2, CDK4, AND CYCLIN D ARE ALSO NOT RESPONSIBLE FOR THE REGULATION OF PULMONARY FIBROBLAST BEHAVIOR BY MIR-338-3P. MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION BY PREVENTING TGFBETA-MEDIATED DOWNREGULATION OF PHOSPHATASE AND TENSIN HOMOLOG (PTEN), A KNOWN ANTIFIBROTIC MEDIATOR. 2022 14 5939 47 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 15 6053 22 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 16 3245 23 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 17 3885 29 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 5988 30 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 19 5995 28 TGFBETA-INDUCED FIBROBLAST ACTIVATION REQUIRES PERSISTENT AND TARGETED HDAC-MEDIATED GENE REPRESSION. TISSUE FIBROSIS IS A CHRONIC DISEASE DRIVEN BY PERSISTENT FIBROBLAST ACTIVATION THAT HAS RECENTLY BEEN LINKED TO EPIGENETIC MODIFICATIONS. HERE, WE SCREENED A SMALL LIBRARY OF EPIGENETIC SMALL-MOLECULE MODULATORS TO IDENTIFY COMPOUNDS CAPABLE OF INHIBITING OR REVERSING TGFBETA-MEDIATED FIBROBLAST ACTIVATION. WE IDENTIFIED PRACINOSTAT, AN HDAC INHIBITOR, AS A POTENT ATTENUATOR OF LUNG FIBROBLAST ACTIVATION AND CONFIRMED ITS EFFICACY IN PATIENT-DERIVED FIBROBLASTS ISOLATED FROM FIBROTIC LUNG TISSUE. MECHANISTICALLY, WE FOUND THAT HDAC-DEPENDENT TRANSCRIPTIONAL REPRESSION WAS AN EARLY AND ESSENTIAL EVENT IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION. TREATMENT OF LUNG FIBROBLASTS WITH PRACINOSTAT BROADLY ATTENUATED TGFBETA-MEDIATED EPIGENETIC REPRESSION AND PROMOTED FIBROBLAST QUIESCENCE. WE CONFIRMED A SPECIFIC ROLE FOR HDAC-DEPENDENT HISTONE DEACETYLATION IN THE PROMOTER REGION OF THE ANTI-FIBROTIC GENE PPARGC1A (PGC1ALPHA) IN RESPONSE TO TGFBETA STIMULATION. FINALLY, WE IDENTIFIED HDAC7 AS A KEY FACTOR WHOSE SIRNA-MEDIATED KNOCKDOWN ATTENUATES FIBROBLAST ACTIVATION WITHOUT ALTERING GLOBAL HISTONE ACETYLATION. TOGETHER, THESE RESULTS PROVIDE NOVEL MECHANISTIC INSIGHT INTO THE ESSENTIAL ROLE HDACS PLAY IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION VIA TARGETED GENE REPRESSION. 2019 20 2817 28 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010