1   766 153 CCL5 SUPPRESSES KLOTHO EXPRESSION VIA P-STAT3/DNA METHYLTRANSFERASE1-MEDIATED PROMOTER HYPERMETHYLATION. BACKGROUND: ENHANCED INFLAMMATION AND REDUCED KLOTHO ARE COMMON FEATURES IN CHRONIC KIDNEY DISEASE (CKD). INFLAMMATION INDUCES DNA HYPERMETHYLATION. THIS STUDY ASSESSED THE PERFORMANCE OF INFLAMMATORY MARKER C-C MOTIF CHEMOKINE 5 (CCL5) IN EPIGENETIC REGULATION OF KLOTHO EXPRESSION. METHODS: FIFTY CKD PATIENTS AND 25 MATCHED CONTROLS WERE ENROLLED, AND SERUM CCL5 LEVEL, SKLOTHO LEVEL, AND DNA METHYLATION WERE EVALUATED IN THESE SUBJECTS. A RENAL INTERSTITIAL FIBROSIS (RIF) MODEL WITH CKD WAS INDUCED IN MICE VIA UNILATERAL URETERAL OBSTRUCTION (UUO) IN VIVO AND HUMAN PROXIMAL TUBULAR EPITHELIAL (HK-2) CELLS TREATED WITH CCL5 IN VITRO. 5-AZA-2'-DEOXYCYTIDINE (5-AZA), A DNA METHYLTRANSFERASE INHIBITOR WAS GIVEN TO UUO MICE. HEMATOXYLIN AND EOSIN (HE) AND MASSON TRICHROME STAINING WERE ADOPTED TO EVALUATE RENAL PATHOLOGICAL CHANGES. METHYLATION-SPECIFIC PCR WAS PERFORMED TO ASSESS DNA METHYLATION OF KLOTHO PROMOTER IN THE PERIPHERAL BLOOD LEUCOCYTES (PBLS) FROM CKD PATIENTS AND OBSTRUCTIVE KIDNEY FROM UUO MICE. CCL5, KLOTHO, AND DNA METHYLTRANSFERASES (DNMTS) WERE DETERMINED BY ELISAS, IMMUNOFLUORESCENCE, OR WESTERN BLOTTING. HK-2 CELLS WERE EXPOSED TO CCL5 WITH OR WITHOUT 5-AZA AND STATTIC, A P-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) INHIBITOR, AND EXPRESSIONS OF P-STAT3, DNMT1, AND KLOTHO WERE DETERMINED BY WESTERN BLOTTING. RESULTS: CCL5 UPREGULATION CONCOMITANT WITH KLOTHO DOWNREGULATION IN SERUM AND GLOBAL DNA METHYLATION IN PBLS WERE OBSERVED IN CKD SAMPLES. UUO CONTRIBUTED TO SEVERE RENAL INTERSTITIAL FIBROSIS AND ENHANCED EXPRESSIONS OF FIBROTIC MARKERS. MOREOVER, UUO INCREASED THE CCL5 LEVEL, INDUCED KLOTHO PROMOTER METHYLATION, SUPPRESSED KLOTHO LEVEL, ACTIVATED P-STAT3 SIGNALING, AND UPREGULATED DNMT1 LEVEL. A SIMILAR OBSERVATION WAS MADE IN HK-2 CELLS TREATED WITH CCL5. MORE IMPORTANTLY, 5-AZA INHIBITED UUO-INDUCED KLOTHO HYPERMETHYLATION, REVERSED KLOTHO, DOWNREGULATED P-STAT3 EXPRESSIONS, AND AMELIORATED RIF IN VIVO. THE CONSISTENT FINDINGS IN VITRO WERE ALSO OBTAINED IN HK-2 CELLS EXPOSED TO 5-AZA AND STATTIC. CONCLUSION: THE CCL5/P-STAT3/DNMT1 AXIS IS IMPLICATED IN EPIGENETIC REGULATION OF KLOTHO EXPRESSION IN CKD. THIS STUDY PROVIDES NOVEL THERAPEUTIC POSSIBILITIES FOR REVERSAL OF KLOTHO SUPPRESSION BY CKD.	2022	

2  3036  45 GENISTEIN AMELIORATES RENAL FIBROSIS THROUGH REGULATION SNAIL VIA M6A RNA DEMETHYLASE ALKBH5. RENAL TUBULE-INTERSTITIAL FIBROSIS IS RELATED TO CHRONIC KIDNEY DISEASE PROGRESSION AND A TYPICAL FEATURE OF THE AGING KIDNEY. EPIGENETIC MODIFICATIONS OF FIBROSIS-PRONE GENES REGULATE THE DEVELOPMENT OF RENAL FIBROSIS. AS A KIND OF "EPIGENETIC DIET", SOY ISOFLAVONE GENISTEIN WAS REPORTED TO HAVE RENAL PROTECTIVE ACTION AND EPIGENETIC-MODULATING EFFECTS. HOWEVER, ITS RENAL PROTECTION ROLE AND UNDERLYING MECHANISMS ARE YET TO BE FULLY CLARIFIED. HEREIN, WE SHOWED THAT GENISTEIN EXHIBITS A DEMONSTRABLE ANTI-FIBROTIC EFFECT ON KIDNEY IN VIVO UUO (UNILATERAL URETERAL OCCLUSION) MODEL AND RENAL EPITHELIAL CELLS IN VITRO MODEL. THE MECHANISM IS STRONGLY ASSOCIATED WITH EPITHELIAL-TO-MESENCHYMAL TRANSITION AND M6A RNA DEMETHYLASE ALKBH5. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO EXHIBITED ADVERSE EXPRESSION OF RENAL FIBROSIS-RELATED PROTEINS AND SIGNIFICANT INCREASES IN THE TOTAL M6A LEVEL. AS AN ERASER, ALKBH5 SHOWED SEVERER SUPPRESSION IN THE RENAL FIBROSIS PROCESS. HOWEVER, GENISTEIN PRETREATMENT RESTORED ALKBH5 LOSS REMARKABLY AND REDUCED RENAL FIBROSIS, ABNORMAL PROTEIN, AND INFLAMMATORY MARKERS. THE EXAMINATION OF POSSIBLE MECHANISMS REVEALED THAT GENISTEIN PROMOTED ALKBH5 AND MAYBE INDUCED THE LEVEL OF MRNA M6A METHYLATION IN SOME EPITHELIAL-TO-MESENCHYMAL TRANSITION-RELATED TRANSCRIPTION FACTORS. WE FOUND SNAIL WAS THE CRITICAL REGULATOR AND CRITICAL FOR THE PROTECTIVE ROLE OF GENISTEIN. TO VERIFY THE RELATIONSHIP BETWEEN ALKBH5 AND SNAIL, WE GENERATED KNOCKDOWN AND OVEREXPRESSION OF ALKBH5 CELLS IN VITRO. ALKBH5 KNOCKDOWN ENHANCED THE MESENCHYMAL PHENOTYPE MARKER ALPHA-SMOOTH MUSCLE ACTIN AND SNAIL EXPRESSION. IN AGREEMENT, OVEREXPRESSION ALKBH5 INCREASED EPITHELIAL ADHESION MOLECULE E-CADHERIN AND REDUCED SNAIL EXPRESSION. IN CONCLUSION, GENISTEIN INCREASED RENAL ALKBH5 EXPRESSION IN UUO-INDUCED RENAL FIBROSIS AND REDUCED RNA M6A LEVELS AND AMELIORATES RENAL DAMAGES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                       
3  3889  43 KLOTHO RECOVERY BY GENISTEIN VIA PROMOTER HISTONE ACETYLATION AND DNA DEMETHYLATION MITIGATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS A COMMON HISTOMORPHOLOGICAL FEATURE OF RENAL AGING AND CHRONIC KIDNEY DISEASES OF ALL ETIOLOGIES, AND ITS INITIATION AND PROGRESSION ARE SUBSTANTIALLY INFLUENCED BY ABERRANT EPIGENETIC MODIFICATIONS OF FIBROSIS-SUSCEPTIBLE GENES, YET WITHOUT EFFECTIVE THERAPY. "EPIGENETIC DIETS" EXHIBIT TISSUE-PROTECTIVE AND EPIGENETIC-MODULATING PROPERTIES; HOWEVER, THEIR ANTI-RENAL FIBROSIS FUNCTIONS AND THE UNDERLYING MECHANISMS ARE LESS UNDERSTOOD. IN THIS STUDY, WE SHOW THAT GENISTEIN, A PHYTOESTROGENIC ISOFLAVONE ENRICHED IN DIETARY SOY PRODUCTS, EXHIBITS IMPRESSIVE ANTI-RENAL FIBROSIS ACTIVITIES BY RECOVERING EPIGENETIC LOSS OF KLOTHO, A KIDNEY-ENRICHED ANTI-AGING AND FIBROSIS-SUPPRESSING PROTEIN. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO (UNILATERAL URETERAL OCCLUSION) DISPLAYED SEVERER KLOTHO SUPPRESSION AND ADVERSE EXPRESSION OF RENAL FIBROSIS-ASSOCIATED PROTEINS, BUT GENISTEIN ADMINISTRATION MARKEDLY RECOVERED THE KLOTHO LOSS AND ATTENUATED RENAL FIBROSIS AND THE PROTEIN EXPRESSION ABNORMALITIES. THE EXAMINATION OF POSSIBLE CAUSES OF THE KLOTHO RECOVERY REVEALED THAT GENISTEIN SIMULTANEOUSLY INHIBITED HISTONE 3 DEACETYLATION OF KLOTHO PROMOTER AND NORMALIZED THE PROMOTER DNA HYPERMETHYLATION BY SUPPRESSING ELEVATED DNA METHYLTRANSFERASE DNMT1 AND DNMT3A. MORE IMPORTANTLY, GENISTEIN'S ANTI-RENAL FIBROSIS EFFECTS ON THE RENAL FIBROTIC LESIONS AND THE ABNORMAL EXPRESSIONS OF FIBROSIS-ASSOCIATED PROTEINS WERE ABROGATED WHEN KLOTHO IS KNOCKDOWN BY RNA INTERFERENCES IN UUO MICE. THUS, OUR RESULTS IDENTIFY KLOTHO RESTORATION VIA EPIGENETIC HISTONE ACETYLATION AND DNA DEMETHYLATION AS A CRITICAL MECHANISM OF GENISTEIN'S ANTI-FIBROSIS FUNCTION AND SHED NEW LIGHTS ON THE POTENTIALS OF EPIGENETIC DIETS IN PREVENTING OR TREATING AGING OR RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. KEY MESSAGES: GENISTEIN PREVENTS RENAL FIBROSIS AND THE ASSOCIATED KLOTHO SUPPRESSION IN UUO MICE. GENISTEIN UPREGULATES KLOTHO IN PART BY REVERSING THE PROMOTER HISTONE 3 HYPOACETYLATION. GENISTEIN ALSO PRESERVES KLOTHO VIA RELIEVING KLOTHO PROMOTER HYPERMETHYLATION. GENISTEIN DEMETHYLATES KLOTHO PROMOTER BY INHIBITING ABERRANT DNMT1/3A EXPRESSION. GENISTEIN RESTORATION OF KLOTHO IS ESSENTIAL FOR ITS ANTI-RENAL FIBROSIS FUNCTION.	2019	
                        
4  6235  54 THE M(6)A DEMETHYLASE FTO PROMOTES RENAL EPITHELIAL-MESENCHYMAL TRANSITION BY REDUCING THE M(6)A MODIFICATION OF LNCRNA GAS5. BACKGROUND: RENAL INTERSTITIAL FIBROSIS (RIF) IS THE MAIN PATHOLOGICAL CHANGE OF A VARIETY OF CHRONIC KIDNEY DISEASES (CKD). EPIGENETIC MODIFICATIONS OF FIBROSIS-PRONE GENES REGULATE RIF PROGRESSION. THIS STUDY AIMED TO INVESTIGATE LONG NON-CODING RNA (LNCRNA) N6-METHYLADENOSINE (M(6)A) MODIFICATION AND ITS ROLE IN REGULATING RIF PROGRESSION. METHODS: UNILATERAL URETERAL OCCLUSION (UUO) WAS EMPLOYED TO CONSTRUCT THE RIF IN VIVO MODEL; AND TGF-BETA1-TREATED HK-2 AND HKC-8 CELLS WERE USED FOR IN VITRO EXPERIMENTS. THE MRNA AND PROTEIN EXPRESSIONS WERE ASSESSED USING QRT-PCR AND WESTERN BLOT. THE PROLIFERATION AND MIGRATION WERE EVALUATED BY EDU ASSAY AND TRANSWELL ASSAY, RESPECTIVELY. IN ADDITION, LEVELS OF INFLAMMATORY CYTOKINES WERE DETERMINED BY ELISA ASSAY AND QRT-PCR. MOREOVER, LNCRNA GAS5 M(6)A LEVEL WAS DETECTED USING ME-RIP ASSAY. HE AND MASSON STAINING WERE EMPLOYED TO EVALUATE FIBROTIC LESIONS OF THE KIDNEY. RESULTS: FTO EXPRESSION WAS ELEVATED IN HK-2 AND HKC-8 CELLS AFTER TGF-BETA1 TREATMENT AND MOUSE KIDNEY TISSUE FOLLOWING UUO, AND LNCRNA GAS5 WAS DOWNREGULATED. LNCRNA GAS5 OVEREXPRESSION OR FTO SILENCING SUPPRESSED TGF-BETA1-INDUCED THE INCREASE OF EMT-RELATED PROTEINS (VIMENTIN, SNAIL AND N-CADHERIN) AND INFLAMMATORY CYTOKINES (IL-6, IL-1BETA AND TNF-ALPHA) LEVELS IN HK-2 CELLS. FTO SUPPRESSED LNCRNA GAS5 EXPRESSION BY REDUCING THE M6A MODIFICATION OF LNCRNA GAS5. ADDITIONALLY, FTO KNOCKDOWN COULD SUPPRESS EMT PROCESS AND INFLAMMATION RESPONSE INDUCED BY TGF-BETA1 AND UUO IN VITRO AND IN VIVO. AS EXPECTED, FTO KNOCKDOWN ABROGATED THE PROMOTION EFFECTS OF LNCRNA GAS5 SILENCING ON TGF-BETA1-INDUCED EMT PROCESS AND INFLAMMATION RESPONSE IN HK-2 AND HKC-8 CELLS. CONCLUSION: FTO PROMOTED EMT PROCESS AND INFLAMMATION RESPONSE THROUGH REDUCING THE M(6)A MODIFICATION OF LNCRNA GAS5.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5  5994  46 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	
                                                                                                                                                                                                                                                                                                                                               
6  6298  42 THE PROTECTIVE EFFECT OF ZEBULARINE, AN INHIBITOR OF DNA METHYLTRANSFERASE, ON RENAL TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. RENAL FIBROSIS, THE FINAL PATHWAY OF CHRONIC KIDNEY DISEASE, IS CAUSED BY GENETIC AND EPIGENETIC MECHANISMS. ALTHOUGH DNA METHYLATION HAS DRAWN ATTENTION AS A DEVELOPING MECHANISM OF RENAL FIBROSIS, ITS CONTRIBUTION TO RENAL FIBROSIS HAS NOT BEEN CLARIFIED. TO ADDRESS THIS ISSUE, THE EFFECT OF ZEBULARINE, A DNA METHYLTRANSFERASE INHIBITOR, ON RENAL INFLAMMATION AND FIBROSIS IN THE MURINE UNILATERAL URETERAL OBSTRUCTION (UUO) MODEL WAS ANALYZED. ZEBULARINE SIGNIFICANTLY ATTENUATED RENAL TUBULOINTERSTITIAL FIBROSIS AND INFLAMMATION. ZEBULARINE DECREASED TRICHROME, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN IV, AND TRANSFORMING GROWTH FACTOR-BETA1 STAINING BY 56.2%. 21.3%, 30.3%, AND 29.9%, RESPECTIVELY, AT 3 DAYS, AND BY 54.6%, 41.9%, 45.9%, AND 61.7%, RESPECTIVELY, AT 7 DAYS AFTER UUO. ZEBULARINE DOWNREGULATED MRNA EXPRESSION LEVELS OF MATRIX METALLOPROTEINASE (MMP)-2, MMP-9, FIBRONECTIN, AND SNAIL1 BY 48.6%. 71.4%, 31.8%, AND 42.4%, RESPECTIVELY, AT 7 DAYS AFTER UUO. ZEBULARINE ALSO SUPPRESSED THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN (IL)-1BETA, AND IL-6, BY 69.8%, 74.9%, AND 69.6%, RESPECTIVELY, IN OBSTRUCTED KIDNEYS. FURTHERMORE, INHIBITING DNA METHYLTRANSFERASE BUTTRESSED THE NUCLEAR EXPRESSION OF NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE FACTOR 2, WHICH UPREGULATED DOWNSTREAM EFFECTORS SUCH AS CATALASE (1.838-FOLD INCREASE AT 7 DAYS, P < 0.01), SUPEROXIDE DISMUTASE 1 (1.494-FOLD INCREASE AT 7 DAYS, P < 0.05), AND NAD(P)H: QUINONE OXIDOREDUATE-1 (1.376-FOLD INCREASE AT 7 DAYS, P < 0.05) IN OBSTRUCTED KIDNEYS. COLLECTIVELY, THESE FINDINGS SUGGEST THAT INHIBITING DNA METHYLATION RESTORES THE DISRUPTED BALANCE BETWEEN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY PATHWAYS TO ALLEVIATE RENAL INFLAMMATION AND FIBROSIS. THEREFORE, THESE RESULTS HIGHLIGHT THE POSSIBILITY OF DNA METHYLTRANSFERASES AS THERAPEUTIC TARGETS FOR TREATING RENAL INFLAMMATION AND FIBROSIS.	2022	
                                                                                                                                                                                                                                                                      
7   594  35 BET PROTEIN INHIBITOR JQ1 MODULATES MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS INDUCED BY CHRONIC KIDNEY DISEASE. AMONG THE MECHANISMS INVOLVED IN THE PROGRESSION OF KIDNEY DISEASE, MITOCHONDRIAL DYSFUNCTION HAS SPECIAL RELEVANCE. EPIGENETIC DRUGS SUCH AS INHIBITORS OF EXTRA-TERMINAL DOMAIN PROTEINS (IBET) HAVE SHOWN BENEFICIAL EFFECTS IN EXPERIMENTAL KIDNEY DISEASE, MAINLY BY INHIBITING PROLIFERATIVE AND INFLAMMATORY RESPONSES. THE IMPACT OF IBET ON MITOCHONDRIAL DAMAGE WAS EXPLORED IN IN VITRO STUDIES IN RENAL CELLS STIMULATED WITH TGF-BETA1 AND IN VIVO IN MURINE UNILATERAL URETERAL OBSTRUCTION (UUO) MODEL OF PROGRESSIVE KIDNEY DAMAGE. IN VITRO, JQ1 PRETREATMENT PREVENTED THE TGF-BETA1-INDUCED DOWNREGULATION OF COMPONENTS OF THE OXIDATIVE PHOSPHORYLATION CHAIN (OXPHOS), SUCH AS CYTOCHROME C AND CV-ATP5A IN HUMAN PROXIMAL TUBULAR CELLS. IN ADDITION, JQ1 ALSO PREVENTED THE ALTERED MITOCHONDRIAL DYNAMICS BY AVOIDING THE INCREASE IN THE DRP-1 FISSION FACTOR. IN UUO MODEL, RENAL GENE EXPRESSION LEVELS OF CYTOCHROME C AND CV-ATP5A AS WELL AS PROTEIN LEVELS OF CYTOCHROME C WERE REDUCED THESE CHANGES WERE PREVENTED BY JQ1 ADMINISTRATION. IN ADDITION, JQ1 DECREASED PROTEIN LEVELS OF THE DRP1 FISSION PROTEIN AND INCREASED THE OPA-1 FUSION PROTEIN, RESTORING MITOCHONDRIAL DYNAMICS. MITOCHONDRIA ALSO PARTICIPATE IN THE MAINTENANCE OF REDOX BALANCE. JQ1 RESTORED THE GENE EXPRESSION OF ANTIOXIDANT PROTEINS, SUCH AS CATALASE AND HEME OXYGENASE 1 IN TGF-BETA1-STIMULATED HUMAN PROXIMAL TUBULAR CELLS AND IN MURINE OBSTRUCTED KIDNEYS. INDEED, IN TUBULAR CELLS, JQ1 DECREASED ROS PRODUCTION INDUCED BY STIMULATION WITH TGF-BETA1, AS EVALUATED BY MITOSOXTM. IBETS, SUCH AS JQ1, IMPROVE MITOCHONDRIAL DYNAMICS, FUNCTIONALITY, AND OXIDATIVE STRESS IN KIDNEY DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  6020  42 THE ATTENUATION OF RENAL FIBROSIS BY HISTONE DEACETYLASE INHIBITORS IS ASSOCIATED WITH THE PLASTICITY OF FOXP3(+)IL-17(+) T CELLS. BACKGROUND: THE HISTONE DEACETYLASE (HDAC) INHIBITOR, WHICH HAS POTENTIAL EFFECTS ON EPIGENETIC MODIFICATIONS, HAD BEEN REPORTED TO ATTENUATE RENAL FIBROSIS. CD4(+) FORKHEAD BOX P3 (FOXP3)(+) T REGULATORY (TREG) CELLS MAY BE CONVERTED TO INFLAMMATION-ASSOCIATED T HELPER 17 CELLS (TH17) WITH TISSUE FIBROSIS PROPERTIES. THE ASSOCIATION BETWEEN FOXP3(+)IL-17(+) T CELLS AND THE ATTENUATION OF RENAL FIBROSIS BY THE HDAC INHIBITOR IS NOT CLEAR. METHODS: THIS STUDY EVALUATED THE ROLES OF THE HDAC INHIBITOR, TREG CELLS AND THEIR DIFFERENTIATION INTO TH17 CELLS, WHICH AGGRAVATE CHRONIC INFLAMMATION AND RENAL FIBROSIS IN A UNILATERAL URETERAL OBSTRUCTION (UUO) MOUSE MODEL. THE STUDY GROUPS INCLUDED CONTROL AND UUO MICE THAT WERE MONITORED FOR 7, 14 OR 21 DAYS. RESULTS: JUXTAGLOMERULAR (JG) HYPERPLASIA, ANGIOTENSIN II TYPE 1 RECEPTOR (AT1R) EXPRESSION AND LYMPHOCYTE INFILTRATION WERE OBSERVED IN RENAL TISSUES AFTER UUO BUT WERE DECREASED AFTER TRICHOSTATIN A (TSA) TREATMENT, A HDAC INHIBITOR. THE NUMBER OF CD4(+)FOXP3(+) T CELLS INCREASED PROGRESSIVELY, ALONG WITH THE NUMBER OF FOXP3(+)INTERLEUKIN (IL)-17(+) T CELLS, AFTER 14 DAYS, AND THEIR NUMBERS THEN PROGRESSIVELY DECREASED WITH INCREASING CD4(+)IL-17(+) T CELL NUMBERS, AS DEMONSTRATED BY DOUBLE IMMUNOHISTOCHEMISTRY. PROGRESSIVE RENAL FIBROSIS WAS ASSOCIATED WITH THE LOSS OF CD4(+)FOXP3(+)IL-17(+) T CELLS IN SPLENIC SINGLE-CELL SUSPENSIONS. FOXP3(+)IL-17(+) T CELLS EXPRESSED TGF-BETA1 BOTH IN VITRO AND IN VIVO, AND TGF-BETA1 EXPRESSION WAS SIGNIFICANTLY KNOCKDOWN BY IL-17 SIRNA IN VITRO. THESE CELLS WERE FOUND TO PLAY A ROLE IN CONVERTING TREGS INTO IL-17- AND TGF-BETA1-PRODUCING CELLS. CONCLUSIONS: TSA TREATMENT DECREASED JG HYPERPLASIA, THE PERCENTAGE OF FOXP3(+)IL-17(+) CELLS AND THE DEGREE OF FIBROSIS, SUGGESTING THAT THERAPEUTIC BENEFITS MAY RESULT FROM EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                          
9  5603  48 ROS PROMOTE HYPER-METHYLATION OF NDRG2 PROMOTERS IN A DNMTS-DEPENDENT MANNER: CONTRIBUTES TO THE PROGRESSION OF RENAL FIBROSIS. RENAL FIBROSIS IS THE COMMON HISTOPATHOLOGICAL FEATURE OF CHRONIC KIDNEY DISEASES (CKD), AND THERE IS INCREASING EVIDENCE THAT EPIGENETIC REGULATION IS INVOLVED IN THE OCCURRENCE AND PROGRESSION OF RENAL FIBROSIS. N-MYC DOWNSTREAM-REGULATED GENE 2 (NDRG2) IS SIGNIFICANTLY DOWN-REGULATED IN RENAL FIBROSIS, THE MECHANISM OF WHICH REMAINS UNCLEAR. PREVIOUS STUDIES HAVE CONFIRMED THAT THE INHIBITION OF NDRG2 EXPRESSION IN TUMOR CELLS IS RELATED TO HYPER-METHYLATION, MAINLY REGULATED BY DNA METHYLTRANSFERASES (DNMTS). HEREIN, WE EXPLORED THE EXPRESSION OF NDRG2 AND ITS EPIGENETIC REGULATORY MECHANISM IN RENAL FIBROSIS. THE RESULTS SHOWED THAT THE EXPRESSION OF NDRG2 WAS SIGNIFICANTLY INHIBITED IN VIVO AND IN VITRO, WHILE THE OVEREXPRESSION OF NDRG2 EFFECTIVELY ALLEVIATED RENAL FIBROSIS. MEANWHILE, WE FOUND THAT THE EXPRESSION OF DNMT1/3A/3B WAS SIGNIFICANTLY INCREASED IN HYPOXIA-INDUCED HK2 CELLS AND UNILATERAL URETERAL OBSTRUCTION (UUO) MICE ACCOMPANIED BY HYPER-METHYLATION OF THE NDGR2 PROMOTER. METHYLTRANSFERASE INHIBITOR (5-AZA-DC) CORRECTED THE ABNORMAL EXPRESSION OF DNMT1/3A/3B, REDUCED THE METHYLATION LEVEL OF NDRG2 PROMOTER AND RESTORED THE EXPRESSION OF NDRG2. THE UPSTREAM EVENTS THAT MEDIATE CHANGES IN NDRG2 METHYLATION WERE FURTHER EXPLORED. REACTIVE OXYGEN SPECIES (ROS) ARE IMPORTANT EPIGENETIC REGULATORS AND HAVE BEEN SHOWN TO PLAY A KEY ROLE IN RENAL INJURY DUE TO VARIOUS CAUSES. ACCORDINGLY, WE FURTHER EXPLORED WHETHER ROS COULD INDUCE DNA-EPIGENETIC CHANGES OF THE EXPRESSION OF NDRG2 AND THEN PARTICIPATED IN THE DEVELOPMENT OF RENAL FIBROSIS. OUR RESULTS SHOWED THAT MITOCHONDRIA-TARGETED ANTIOXIDANTS (MITO-TEMPO) COULD REVERSE THE EPIGENETIC INHIBITION OF NDRG2 IN A DNMT-SENSITIVE MANNER, SHOWING STRONG ABILITY OF DNA DEMETHYLATION, EXHIBITING EPIGENETIC REGULATION AND ANTI-FIBROSIS EFFECTS SIMILAR TO 5-AZA-DC. MORE IMPORTANTLY, THE ANTI-FIBROTIC EFFECTS OF 5-AZA-DC AND MITO-TEMPO WERE ELIMINATED IN HK2 CELLS WITH NDRG2 KNOCKDOWN. THESE FINDINGS HIGHLIGHT THAT TARGETING ROS-MEDIATED HYPER-METHYLATION OF NDRG2 PROMOTER IS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR RENAL FIBROSIS, WHICH WILL PROVIDE NEW INSIGHTS INTO THE TREATMENT OF CKD.	2023	
                                                                
10  1632  41 DNMTS ARE INVOLVED IN TGF-BETA1-INDUCED EPITHELIAL-MESENCHYMAL TRANSITIONS IN AIRWAY EPITHELIAL CELLS. CHRONIC RHINOSINUSITIS (CRS) PATHOGENESIS IS CLOSELY RELATED TO TISSUE REMODELING, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION (EMT). EPIGENETIC MECHANISMS PLAY KEY ROLES IN EMT. DNA METHYLATION, MEDIATED BY DNA METHYLTRANSFERASES (DNMTS), IS AN EPIGENETIC MARKER THAT IS CRITICAL TO EMT. THE GOAL OF THIS STUDY WAS TO DETERMINE WHETHER DNMTS WERE INVOLVED IN TGF-BETA1-INDUCED EMT AND ELUCIDATE THE UNDERLYING MECHANISMS IN NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION AND DNMT ACTIVITY WERE QUANTIFIED. DNMT EXPRESSION WAS MEASURED USING REAL-TIME PCR (QRT-PCR) IN HUMAN CRS TISSUES. MRNA AND PROTEIN LEVELS OF DNMTS, E-CADHERIN, VIMENTIN, ALPHA-SMA, AND FIBRONECTIN WERE DETERMINED USING RT-PCR AND WESTERN BLOTTING, RESPECTIVELY. DNMT1, DNMT3A, AND DNMT3B GENE EXPRESSION WERE KNOCKED DOWN USING SIRNA TRANSFECTION. MAPK PHOSPHORYLATION AND EMT-RELATED TRANSCRIPTION FACTOR LEVELS WERE DETERMINED USING WESTERN BLOTTING. SIGNALING PATHWAYS WERE ANALYZED USING SPECIFIC INHIBITORS OF MAPK. WE DEMONSTRATED THESE DATA IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION, DNMT ACTIVITY, AND DNMT EXPRESSION INCREASED IN CRS TISSUES. DNMT EXPRESSION WAS POSITIVELY CORRELATED WITH LUND-MCKAY CT SCORES. TGF-BETA1 DOSE-DEPENDENTLY INDUCED DNMT EXPRESSION. FURTHER, 5-AZA INHIBITED TGF-BETA1-INDUCED DNMT, SNAIL, AND SLUG EXPRESSION RELATED TO EMT, AS WELL AS P38 AND JNK PHOSPHORYLATION IN A549 CELLS AND TGF-BETA1-INDUCED DNMT EXPRESSION AND EMT IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. TGF-BETA1-INDUCED DNMT EXPRESSION LEADS TO DNA METHYLATION AND EMT VIA P38, JNK, SNAIL, AND SLUG SIGNALING PATHWAYS. INHIBITION OF DNMT SUPPRESSED THE EMT PROCESS AND THEREFORE IS POTENTIALLY A CRS THERAPEUTIC STRATEGY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  3655  38 INDOXYL SULFATE ENHANCE THE HYPERMETHYLATION OF KLOTHO AND PROMOTE THE PROCESS OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A STATE OF KLOTHO DEFICIENCY. THE KLOTHO EXPRESSION MAY BE SUPPRESSED DUE TO DNA HYPERMETHYLATION IN CANCER CELLS SO WE HAVE INVESTIGATED THE EFFECTS AND POSSIBLE MECHANISMS BY WHICH KLOTHO EXPRESSION IS REGULATED IN HUMAN AORTIC SMOOTH MUSCLE CELLS (HASMCS). THE VASCULAR KLOTHO HYPERMETHYLATION IN RADIAL ARTERIES OF PATIENTS WITH END-STAGE RENAL DISEASE WAS DESCRIBED. CULTURED HASMCS AND 5/6-NEPHRECTOMIZED SPRAGUE DAWLEY (SD) RATS TREATED WITH INDOXYL SULFATE (IS) WERE USED AS IN VITRO AND IN VIVO MODELS, RESPECTIVELY. IS INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN HASMCS, AND POTENTIATED HASMCS CALCIFICATION. THE EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) 1 AND 3A IN HASMCS TREATED WITH IS WAS SIGNIFICANTLY INCREASED AND SPECIFIC INHIBITION OF DNA METHYLTRANSFERASE 1 BY 5-AZA-2'-DEOXYCYTIDINE(5AZA-2DC) CAUSED DEMETHYLATION OF THE KLOTHO GENE AND INCREASED KLOTHO EXPRESSION. IN RATS, INJECTION OF IS POTENTIATED VASCULAR CALCIFICATION, INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN THE AORTIC MEDIAL LAYER AND ALL OF THESE CHANGES COULD BE REVERTED BY 5AZA-2DC TREATMENT. TRANSCRIPTIONAL SUPPRESSION OF VASCULAR KLOTHO GENE EXPRESSION BY IS AND EPIGENETIC MODIFICATION OF KLOTHO BY IS MAY BE AN IMPORTANT PATHOLOGICAL MECHANISM OF VASCULAR CALCIFICATION IN CKD.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  3048  37 GENOME-WIDE ANALYSIS REVEALED THAT DZNEP REDUCES TUBULOINTERSTITIAL FIBROSIS VIA DOWN-REGULATION OF PRO-FIBROTIC GENES. TUBULOINTERSTITIAL FIBROSIS HAS BEEN RECENTLY REPORTED TO BE CAUSED BY THE COLLAPSE OF THE EPIGENETIC REGULATION OF KIDNEY DISEASES. WE EXAMINED WHETHER PHARMACOLOGICAL INHIBITION OF HISTONE MODIFICATION IS EFFECTIVE AGAINST RENAL FIBROSIS. DZNEP (3-DEAZANEPLANOCIN A) WAS ORIGINALLY DEVELOPED AS AN ANTI-CANCER DRUG TO INHIBIT THE REPRESSIVE HISTONE MARK, H3K27ME3. WE USED A MODEL OF CHRONIC TUBULOINTERSTITIAL FIBROSIS INDUCED BY UNILATERAL ISCHAEMIA/REPERFUSION AND ADMINISTERED DZNEP INTRAVENOUSLY TO THE MICE FOR 8 WEEKS. WE FOUND DZNEP CONTRIBUTES TO THE REDUCTION OF TUBULOINTERSTITIAL FIBROSIS. WE SELECTED ONLY TUBULAR CELLS FROM IN VIVO SAMPLES USING LASER-CAPTURE MICRODISSECTION BECAUSE EPIGENETIC REGULATION IS SPECIFIC TO THE CELL TYPES, AND WE FOCUSED ON THE CHANGES IN THE TUBULAR CELLS. WE PERFORMED A GENOME-WIDE ANALYSIS OF TUBULAR CELLS USING HIGH-THROUGHPUT SEQUENCING (RNA-SEQ) TO IDENTIFY NOVEL EPIGENETIC FACTORS ASSOCIATED WITH RENAL FIBROSIS. WE FOUND THAT PRO-FIBROTIC GENES SUCH AS COL3A1 (COLLAGEN TYPE 3A1) AND TIMP2 (TISSUE INHIBITOR OF METALLOPROTEINASE 2) WERE SUPPRESSED BY DZNEP IN VIVO. IN ADDITION, PRO-FIBROTIC GENES SUCH AS COL4A1 (COLLAGEN TYPE 4A1), TIMP2 AND MMP14 WERE DOWN-REGULATED BY DZNEP IN VITRO. IN CONCLUSION, WE FOUND THAT PHARMACOLOGICAL EPIGENETIC MODIFICATION BY DZNEP DECREASED THE EXPRESSION LEVELS OF FIBROGENIC GENES IN TUBULAR CELLS AND INHIBITED TUBULOINTERSTITIAL FIBROSIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13  5504  35 RHEIN REVERSAL OF DNA HYPERMETHYLATION-ASSOCIATED KLOTHO SUPPRESSION AMELIORATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS THE HALLMARK OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS. RHEIN, A PLANT-DERIVED ANTHRAQUINONE, DISPLAYS STRONG ANTI-FIBROSIS PROPERTIES, BUT ITS PROTECTIVE MODE OF ACTION REMAINS INCOMPLETELY UNDERSTOOD. HERE WE EXPLORE THE MECHANISM OF RHEIN ANTI-RENAL FIBROSIS BY INVESTIGATING ITS REGULATION OF KLOTHO, A KNOWN RENAL ANTI-FIBROTIC PROTEIN WHOSE SUPPRESSION AFTER RENAL INJURY REPORTEDLY INVOLVES ABERRANT DNA METHYLATION. WE REPORT THAT RHEIN IS AN IMPRESSIVE UP-REGULATOR OF KLOTHO AND IT MARKEDLY REVERSED KLOTHO DOWN-REGULATION IN UNILATERAL URETERAL OCCLUSION-INDUCED FIBROTIC KIDNEY. FURTHER EXAMINATIONS REVEALED THAT KLOTHO LOSS IN FIBROTIC KIDNEY IS ASSOCIATED WITH KLOTHO PROMOTER HYPERMETHYLATION DUE TO ABERRANT METHYLTRANSFERASE 1 AND 3A EXPRESSIONS. HOWEVER, RHEIN SIGNIFICANTLY CORRECTED ALL THESE EPIGENETIC ALTERATIONS AND SUBSEQUENTLY ALLEVIATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS, WHEREAS KLOTHO KNOCKDOWN VIA RNA INTERFERENCES LARGELY ABROGATED THE ANTI-RENAL FIBROTIC EFFECTS OF RHEIN, SUGGESTING THAT RHEIN EPIGENETIC REVERSAL OF KLOTHO LOSS REPRESENTS A CRITICAL MODE OF ACTION THAT CONFERS RHEIN'S ANTI- RENAL FIBROTIC FUNCTIONS. ALTOGETHER OUR STUDIES UNCOVER A NOVEL HYPOMETHYLATING CHARACTER OF RHEIN IN PREVENTING KLOTHO LOSS AND RENAL FIBROSIS, AND DEMONSTRATE THE EFFICACY OF KLOTHO-TARGETED EPIGENETIC INTERVENTION IN POTENTIAL TREATMENT OF RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  6456  33 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  1665  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  5764  40 SORAFENIB ATTENUATES FIBROTIC HEPATIC INJURY THROUGH MEDIATING LYSINE CROTONYLATION. BACKGROUND: LIVER FIBROSIS IS AN INDEPENDENT CONTRIBUTOR OF CHRONIC LIVER DISEASES, AND REGRESSING LIVER FIBROSIS IS CONSIDERED A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC LIVER DISEASES. WE AIMED TO EXPLORE THE EFFECTS AND MECHANISM OF SORAFENIB IN LIVER FIBROSIS. METHODS: MALE SPRAGUE DAWLEY (SD) RATS WERE SUBJECTED TO SUBCUTANEOUS INJECTION OF CARBON TETRACHLORIDE (CCL(4)) FOR 8 WEEKS TO INDUCE LIVER FIBROSIS AND THEN TREATED WITH SORAFENIB. THE DEGREE OF LIVER FIBROSIS WAS ANALYZED BY HEMATOXYLIN-EOSIN (H&E) STAINING, MASSON STAINING, AND PICROSIRIUS RED (PSR) STAINING. SERUM BIOCHEMICAL INDEXES WERE DETECTED BY FULLY AUTOMATIC BIOCHEMICAL ANALYZER OR ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS PERFORMED TO DETECT THE EXPRESSION OF PRO-FIBROTIC GENES. IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOTTING WERE CARRIED OUT TO EVALUATE THE LEVELS OF LYSINE CROTONYLATION. RESULTS: LIVER INDEX WAS REDUCED WITH ORAL SORAFENIB IN CCL(4)-INDUCED RATS. SERUM LIVER FUNCTION (ALANINE AMINOTRANSFERASE (ALT), ASPARTATE AMINOTRANSFERASE (AST), AND TOTAL BILIRUBIN (TBIL)) AND FIBROSIS INDICATORS (TYPE III PROCOLLAGEN (PC-III), HYALURONIC ACID (HA), AND LAMININ (LN)) WERE ATTENUATED WITH SORAFENIB TREATMENT. SORAFENIB IMPROVED THE HEPATIC STRUCTURE AND FIBROTIC PROGRESSION. THE EXPRESSION OF FIBROSIS-RELATED GENES WAS REMARKELY REDUCED WITH SORAFENIB TREATMENT. MEANWHILE, SORAFENIB INHIBITED ALPHA-SMA AND COLLAGEN I CUMULATION INDUCED BY CCL(4) INJECTION. BESIDES, PROTEIN LYSINE CROTONYLATION ESPECIALLY THE CROTONYLATED H2BK12 (H2BK12CR) AND CROTONYLATED H3K18 (H3K18CR) WERE REVERSED BY SORAFENIB, WHICH WERE DECREASED IN RESPONSE TO CCL(4) TREATMENT. SPEARMAN CORRELATION ANALYSIS SHOWN LYSINE CROTONYLATION EXPRESSION WAS NEGATIVELY CORRELATED WITH SERUM FIBROTIC INDICATORS. CONVERSELY, CROTONYLATION-REGULATED ENZYMES, WHICH NEGATIVELY REGULATE PROTEIN CROTONYLATION, WERE INCREASED IN RESPONSE TO CCL(4) TREATMENT, WHILE SORAFENIB REDUCED THEIR EXPRESSION. CONCLUSION: SORAFENIB EXERTS SIGNIFICANT ANTI-FIBROTIC EFFECTS THROUGH MEDIATING CROTONYLATION-REGULATED ENZYMES AND PROTEIN CROTONYLATION IN FIBROTIC RATS.	2022	
                                                                                                           
17  1826  44 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                          
18  2001  26 EPIGENETIC AND NON-EPIGENETIC REGULATION OF KLOTHO IN KIDNEY DISEASE. KLOTHO IS A NOVEL RENOPROTECTIVE ANTI-AGING PROTEIN AVAILABLE IN MEMBRANE-BOUND OR SOLUBLE FORM. KLOTHO IS EXPRESSED IN BRAIN, PANCREAS, AND OTHER SOLID ORGANS BUT SHOWS HIGHEST EXPRESSION LEVELS IN THE KIDNEY. KLOTHO SUSTAINS NORMAL KIDNEY PHYSIOLOGY BUT KLOTHO REGULATION ALSO CONTRIBUTES TO THE PROGRESSION OF KIDNEY DISEASE. SYSTEMIC AND INTRARENAL LEVELS OF KLOTHO FALL DRASTICALLY DURING ACUTE KIDNEY INJURY, KIDNEY FIBROSIS, DIABETIC NEPHROPATHY, AND OTHER FORMS OF CHRONIC KIDNEY DISEASE, ETC. MOREOVER, EXOGENOUS SUPPLEMENTATION OR OVEREXPRESSION OF ENDOGENOUS KLOTHO ATTENUATES KIDNEY DISEASE. THE REGULATION OF ENDOGENOUS KLOTHO EXPRESSION INVOLVES EPIGENETIC AS WELL AS NON-EPIGENETIC MECHANISMS. THE EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS, MIRNAS REGULATE THE CHANGE IN KLOTHO EXPRESSION IN KIDNEY DISEASE. NON-EPIGENETIC MECHANISMS SUCH AS ER STRESS, WNT SIGNALING, ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS), EXCESSIVE REACTIVE OXYGEN SPECIES AND CYTOKINE GENERATION, ALBUMIN OVERLOAD, AND PPAR-GAMMA SIGNALING ALSO CONTRIBUTE TO KLOTHO REGULATION. EVOLVING EVIDENCE HIGHLIGHT THE CAPACITY OF NATURAL PRODUCTS TO REGULATE KLOTHO EXPRESSION IN KIDNEY DISEASE. ALL THESE PRECLINICAL DATA SUGGEST THAT KLOTHO COULD BE A NOVEL BIOMARKER AS WELL AS THERAPEUTIC TARGET. HERE WE REVIEW THE DIFFERENT MECHANISMS OF KLOTHO REGULATION IN THE CONTEXT OF KLOTHO AS A BIOMARKER AND POTENTIAL THERAPEUTIC AGENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  3887  23 KLOTHO METHYLATION IS LINKED TO UREMIC TOXINS AND CHRONIC KIDNEY DISEASE. EPIGENETIC REGULATION PLAYS A MAJOR ROLE IN UREMIC TOXIN-INDUCED CHRONIC KIDNEY DISEASE (CKD) PROGRESSION. THE KLOTHO PROTEIN IS A KEY MODULATOR OF HOMEOSTASIS IN RENAL FUNCTION. UREMIC TOXIN ACCUMULATION CAN INDUCE DNA METHYLTRANSFERASE (DNMT) PROTEIN EXPRESSION, WHICH IS INVOLVED IN THE SILENCING OF KLOTHO THROUGH HYPERMETHYLATION. TREATMENT WITH DNMT INHIBITORS CAN INDUCE A HYPERMETHYLATED STATUS OF KLOTHO AND SUPPRESS MRNA AND PROTEIN EXPRESSION. EPIGENETIC TARGETING OF SPECIFIC GENES MAY BECOME AN EFFECTIVE STRATEGY TO PREVENT PROGRESSION OF UREMIA-RELATED CKD.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  5733  27 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