1 1690 106 DUAL ROLES OF CHROMATIN REMODELING PROTEIN BRG1 IN ANGIOTENSIN II-INDUCED ENDOTHELIAL-MESENCHYMAL TRANSITION. ENDOTHELIAL-MESENCHYMAL TRANSITION (ENDMT) IS CONSIDERED ONE OF THE PROCESSES UNDERLYING TISSUE FIBROSIS BY CONTRIBUTING TO THE POOL OF MYOFIBROBLASTS. IN THE PRESENT STUDY, WE INVESTIGATED THE EPIGENETIC MECHANISM WHEREBY ANGIOTENSIN II (ANG II) REGULATES ENDMT TO PROMOTE CARDIAC FIBROSIS FOCUSING ON THE ROLE OF CHROMATIN REMODELING PROTEIN BRG1. BRG1 KNOCKDOWN OR INHIBITION ATTENUATED ANG II-INDUCED ENDMT, AS EVIDENCED BY DOWN-REGULATION OF CDH5, AN ENDOTHELIAL MARKER, AND UP-REGULATION OF COL1A2, A MESENCHYMAL MARKER, IN CULTURED VASCULAR ENDOTHELIAL CELLS. ON THE ONE HAND, BRG1 INTERACTED WITH AND WAS RECRUITED BY SP1 TO THE SNAI2 (ENCODING SLUG) PROMOTER TO ACTIVATE SNAI2 TRANSCRIPTION IN RESPONSE TO ANG II STIMULATION. ONCE ACTIVATED, SLUG BOUND TO THE CDH5 PROMOTER TO REPRESS CDH5 TRANSCRIPTION. ON THE OTHER HAND, BRG1 INTERACTED WITH AND WAS RECRUITED BY SRF TO THE COL1A2 PROMOTER TO ACTIVATE COL1A2 TRANSCRIPTION. MECHANISTICALLY, BRG1 EVICTED HISTONES FROM THE TARGET PROMOTERS TO FACILITATE THE BINDINGS OF SP1 AND SRF. FINALLY, ENDOTHELIAL CONDITIONAL BRG1 KNOCKOUT MICE (CKO) EXHIBITED A REDUCTION IN CARDIAC FIBROSIS, COMPARED TO THE WILD TYPE (WT) LITTERMATES, IN RESPONSE TO CHRONIC ANG II INFUSION. IN CONCLUSION, OUR DATA DEMONSTRATE THAT BRG1 IS A KEY TRANSCRIPTIONAL COORDINATOR PROGRAMMING ANG II-INDUCED ENDMT TO CONTRIBUTE TO CARDIAC FIBROSIS. 2020 2 5860 33 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2. 2021 3 4016 25 LOW-DOSE HYDRALAZINE PREVENTS FIBROSIS IN A MURINE MODEL OF ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) AND PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD) ARE INTRINSICALLY TIED SYNDROMES. IN THIS REGARD, THE ACUTELY INJURED KIDNEY OFTEN DOES NOT ACHIEVE ITS FULL REGENERATIVE CAPACITY AND AKI DIRECTLY TRANSITIONS INTO PROGRESSIVE CKD ASSOCIATED WITH TUBULOINTERSTITIAL FIBROSIS. UNDERLYING MECHANISMS OF SUCH AKI-TO-CKD PROGRESSION ARE STILL INCOMPLETELY UNDERSTOOD AND SPECIFIC THERAPEUTIC INTERVENTIONS ARE STILL ELUSIVE. BECAUSE EPIGENETIC MODIFICATIONS PLAY A ROLE IN MAINTAINING TISSUE FIBROSIS, WE USED A MURINE MODEL OF ISCHEMIA-REPERFUSION INJURY TO DETERMINE WHETHER ABERRANT PROMOTER METHYLATION OF RASAL1 CONTRIBUTES CAUSALLY TO THE SWITCH BETWEEN PHYSIOLOGICAL REGENERATION AND TUBULOINTERSTITIAL FIBROGENESIS, A HALLMARK OF AKI-TO-CKD PROGRESSION. IT IS KNOWN THAT THE ANTIHYPERTENSIVE DRUG HYDRALAZINE HAS DEMETHYLATING ACTIVITY, AND THAT ITS OPTIMUM DEMETHYLATING ACTIVITY OCCURS AT CONCENTRATIONS BELOW BLOOD PRESSURE-LOWERING DOSES. ADMINISTRATION OF LOW-DOSE HYDRALAZINE EFFECTIVELY INDUCED EXPRESSION OF HYDROXYLASE TET3, WHICH CATALYZED RASAL1 HYDROXYMETHYLATION AND SUBSEQUENT RASAL1 PROMOTER DEMETHYLATION. HYDRALAZINE-INDUCED CPG PROMOTER DEMETHYLATION SUBSEQUENTLY ATTENUATED RENAL FIBROSIS AND PRESERVED EXCRETORY RENAL FUNCTION INDEPENDENT OF ITS BLOOD PRESSURE-LOWERING EFFECTS. IN COMPARISON, RASAL1 DEMETHYLATION AND INHIBITION OF TUBULOINTERSTITIAL FIBROSIS WAS NOT DETECTED UPON ADMINISTRATION OF THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR RAMIPRIL IN THIS MODEL. THUS, RASAL1 PROMOTER METHYLATION AND SUBSEQUENT TRANSCRIPTIONAL RASAL1 SUPPRESSION PLAYS A CAUSAL ROLE IN AKI-TO-CKD PROGRESSION. 2017 4 6446 26 THERAPEUTIC INSIGHTS IN CHRONIC KIDNEY DISEASE PROGRESSION. CHRONIC KIDNEY DISEASE (CKD) HAS BEEN RECOGNIZED AS A LEADING PUBLIC HEALTH PROBLEM WORLDWIDE. THROUGH ITS EFFECT ON CARDIOVASCULAR RISK AND END-STAGE KIDNEY DISEASE, CKD DIRECTLY AFFECTS THE GLOBAL BURDEN OF MORBIDITY AND MORTALITY. CLASSICAL OPTIMAL MANAGEMENT OF CKD INCLUDES BLOOD PRESSURE CONTROL, TREATMENT OF ALBUMINURIA WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR ANGIOTENSIN II RECEPTOR BLOCKERS, AVOIDANCE OF POTENTIAL NEPHROTOXINS AND OBESITY, DRUG DOSING ADJUSTMENTS, AND CARDIOVASCULAR RISK REDUCTION. DIABETES MIGHT ACCOUNT FOR MORE THAN HALF OF CKD BURDEN, AND OBESITY IS THE MOST IMPORTANT PROMPTED FACTOR FOR THIS DISEASE. NEW ANTIHYPERGLYCEMIC DRUGS, SUCH AS SODIUM-GLUCOSE-COTRANSPORTER 2 INHIBITORS HAVE SHOWN TO SLOW THE DECLINE OF GFR, BRINGING ADDITIONAL BENEFIT IN WEIGHT REDUCTION, CARDIOVASCULAR, AND OTHER KIDNEY OUTCOMES. ON THE OTHER HAND, A NEW GENERATION OF NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST HAS RECENTLY BEEN DEVELOPED TO OBTAIN A SELECTIVE RECEPTOR INHIBITION REDUCING SIDE EFFECTS LIKE HYPERKALEMIA AND THEREBY MAKING THE DRUGS SUITABLE FOR ADMINISTRATION TO CKD PATIENTS. MOREOVER, TWO NEW POTASSIUM-LOWERING THERAPIES HAVE SHOWN TO IMPROVE TOLERANCE, ALLOWING FOR HIGHER DOSAGE OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND THEREFORE ENHANCING THEIR NEPHROPROTECTIVE EFFECT. REGARDLESS OF ITS CAUSE, CKD IS CHARACTERIZED BY REDUCED RENAL REGENERATION CAPACITY, MICROVASCULAR DAMAGE, OXIDATIVE STRESS AND INFLAMMATION, RESULTING IN FIBROSIS AND PROGRESSIVE, AND IRREVERSIBLE NEPHRON LOSS. THEREFORE, A HOLISTIC APPROACH SHOULD BE TAKEN TARGETING THE DIVERSE PROCESSES AND BIOLOGICAL CONTEXTS THAT ARE ASSOCIATED WITH CKD PROGRESSION. TO DATE, THERAPEUTIC INTERVENTIONS WHEN TUBULOINTERSTITIAL FIBROSIS IS ALREADY ESTABLISHED HAVE PROVED TO BE INSUFFICIENT, THUS RESEARCH EFFORT SHOULD FOCUS ON UNRAVELING EARLY DISEASE MECHANISMS. AN ARRAY OF NOVEL THERAPEUTIC APPROACHES TARGETING EPIGENETIC REGULATORS ARE NOW UNDERGOING PHASE II OR PHASE III TRIALS AND MIGHT PROVIDE A SIMULTANEOUS REGULATORY ACTIVITY THAT COORDINATELY REGULATE DIFFERENT ASPECTS OF CKD PROGRESSION. 2021 5 4971 22 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 6 6648 20 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 7 2001 25 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 8 6318 25 THE RENIN-ANGIOTENSIN SYSTEM AND REACTIVE OXYGEN SPECIES: IMPLICATIONS IN PANCREATITIS. SIGNIFICANCE: THE RENIN-ANGIOTENSIN SYSTEM (RAS) IS A CIRCULATING HORMONAL SYSTEM INVOLVED IN THE REGULATION OF BLOOD PRESSURE AND CIRCULATING FLUID ELECTROLYTES. RECENT FINDINGS HAVE REVEALED THAT LOCALLY GENERATED ANGIOTENSIN (ANG) II PLAYS A PIVOTAL ROLE IN NORMAL PHYSIOLOGY AS WELL AS PATHOPHYSIOLOGY IN VARIOUS TISSUES AND ORGANS, INCLUDING THE PANCREAS. THIS REVIEW ARTICLE SUMMARIZES CURRENT PROGRESS THAT HAS BEEN MADE IN ELUCIDATING THE PUTATIVE ROLES OF ANG II IN BOTH ACUTE AND CHRONIC PANCREATITIS. RECENT ADVANCES: A CONVERGENCE OF EVIDENCE SUGGESTS THAT THE UNDERLYING MECHANISM MAY INVOLVE REACTIVE OXYGEN SPECIES (ROS)-GENERATING SYSTEMS, SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE, AND SUBSEQUENT ELEVATION OF PROINFLAMMATORY AND PROFIBROGENIC GENE EXPRESSION AS WELL AS PROTEIN ACTIVITY. MORE IMPORTANTLY, ANG II-INDUCED ROS INTERACTS WITH OTHER ROS-GENERATING SYSTEMS TO POSITIVELY FEED-FORWARD THE ROS-INDUCED SIGNALING. CRITICAL ISSUES AND FUTURE DIRECTIONS: ADVANCES IN BASIC RESEARCH INDICATE THAT RAS BLOCKERS MAY PROVIDE POTENTIAL THERAPEUTIC ROLE FOR THE MANAGEMENT OF PANCREATIC INFLAMMATION AND, MORE IMPORTANTLY, PANCREATITIS-ASSOCIATED COMPLICATIONS. GENETIC ALTERATIONS RESULTING FROM A MALFUNCTION IN THE EPIGENETIC CONTROL OF PANCREATIC RAS COULD BE A CAUSATIVE FACTOR IN THE DEVELOPMENT OF PANCREATITIS. 2011 9 5442 24 RENIN-ANGIOTENSIN BLOCKADE RESETS PODOCYTE EPIGENOME THROUGH KRUPPEL-LIKE FACTOR 4 AND ATTENUATES PROTEINURIA. PROTEINURIA IS A CENTRAL COMPONENT OF CHRONIC KIDNEY DISEASE AND AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. KIDNEY PODOCYTES HAVE AN ESSENTIAL ROLE AS A FILTRATION BARRIER AGAINST PROTEINURIA. KRUPPEL-LIKE FACTOR 4 (KLF4) IS EXPRESSED IN PODOCYTES AND DECREASED IN GLOMERULAR DISEASES LEADING TO METHYLATION OF THE NEPHRIN PROMOTER, DECREASED NEPHRIN EXPRESSION AND PROTEINURIA. TREATMENT WITH AN ANGIOTENSIN RECEPTOR BLOCKER (ARB) REDUCED METHYLATION OF THE NEPHRIN PROMOTER IN MURINE GLOMERULI OF AN ADRIAMYCIN NEPHROPATHY MODEL WITH RECOVERY OF KLF4 EXPRESSION AND A DECREASE IN ALBUMINURIA. IN PODOCYTE-SPECIFIC KLF4 KNOCKOUT MICE, THE EFFECT OF ARB ON ALBUMINURIA AND THE NEPHRIN PROMOTER METHYLATION WAS ATTENUATED. IN CULTURED HUMAN PODOCYTES, ANGIOTENSIN II REDUCED KLF4 EXPRESSION AND CAUSED METHYLATION OF THE NEPHRIN PROMOTER WITH DECREASED NEPHRIN EXPRESSION. IN PATIENTS, NEPHRIN PROMOTER METHYLATION WAS INCREASED IN PROTEINURIC KIDNEY DISEASES WITH DECREASED KLF4 AND NEPHRIN EXPRESSION. KLF4 EXPRESSION IN ARB-TREATED PATIENTS WAS HIGHER IN PATIENTS WITH THAN WITHOUT ARB TREATMENT. THUS, ANGIOTENSIN II CAN MODULATE EPIGENETIC REGULATION IN PODOCYTES AND ARB INHIBITS THESE ACTIONS IN PART VIA KLF4 IN PROTEINURIC KIDNEY DISEASES. THIS STUDY PROVIDES A NEW CONCEPT THAT RENIN-ANGIOTENSIN SYSTEM BLOCKADE CAN EXERT THERAPEUTIC EFFECTS THROUGH EPIGENETIC MODULATION OF THE KIDNEY GENE EXPRESSION. 2015 10 4017 24 LOW-DOSE HYDRALAZINE REDUCES ALBUMINURIA AND GLOMERULOSCLEROSIS IN A MOUSE MODEL OF OBESITY-RELATED CHRONIC KIDNEY DISEASE. AIM: TO DETERMINE, USING A MOUSE MODEL OF OBESITY, WHETHER LOW-DOSE HYDRALAZINE PREVENTS OBESITY-RELATED CHRONIC KIDNEY DISEASE (CKD). METHODS: FROM 8 WEEKS OF AGE, MALE C57BL/6 MICE RECEIVED A HIGH-FAT DIET (HFD) OR CHOW, WITH OR WITHOUT LOW-DOSE HYDRALAZINE (25 MG/L) IN DRINKING WATER, FOR 24 WEEKS. BIOMETRIC AND METABOLIC VARIABLES, RENAL FUNCTION AND STRUCTURAL CHANGES, RENAL GLOBAL DNA METHYLATION, DNA METHYLATION PROFILE AND MARKERS OF RENAL FIBROSIS, INJURY, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED. RESULTS: THE HFD-FED MICE DEVELOPED OBESITY, WITH GLUCOSE INTOLERANCE, HYPERINSULINAEMIA AND DYSLIPIDAEMIA. OBESITY INCREASED ALBUMINURIA AND GLOMERULOSCLEROSIS, WHICH WERE SIGNIFICANTLY AMELIORATED BY LOW-DOSE HYDRALAZINE IN THE ABSENCE OF A BLOOD PRESSURE-LOWERING EFFECT. OBESITY INCREASED RENAL GLOBAL DNA METHYLATION AND THIS WAS ATTENUATED BY LOW-DOSE HYDRALAZINE. HFD-INDUCED CHANGES IN METHYLATION OF INDIVIDUAL LOCI WERE ALSO SIGNIFICANTLY REVERSED BY LOW-DOSE HYDRALAZINE. OBESE MICE DEMONSTRATED INCREASED MARKERS OF KIDNEY FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS, BUT THESE MARKERS WERE NOT SIGNIFICANTLY IMPROVED BY HYDRALAZINE. CONCLUSION: LOW-DOSE HYDRALAZINE AMELIORATED HFD-INDUCED ALBUMINURIA AND GLOMERULOSCLEROSIS, INDEPENDENT OF ALTERATIONS IN BIOMETRIC AND METABOLIC VARIABLES OR BLOOD PRESSURE REGULATION. ALTHOUGH THE PRECISE MECHANISM OF RENOPROTECTION IN OBESITY IS UNCLEAR, AN EPIGENETIC BASIS MAY BE IMPLICATED. THESE DATA SUPPORT REPURPOSING HYDRALAZINE AS A NOVEL THERAPY TO PREVENT CKD PROGRESSION IN OBESE PATIENTS. 2022 11 3431 31 HYDROGEN SULFIDE ALLEVIATES HYPERTENSIVE KIDNEY DYSFUNCTION THROUGH AN EPIGENETIC MECHANISM. HYPERTENSION IS A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD), AND RENAL INFLAMMATION IS AN INTEGRAL PART IN THIS PATHOLOGY. HYDROGEN SULFIDE (H(2)S) HAS BEEN SHOWN TO MITIGATE RENAL DAMAGE THROUGH REDUCTION IN BLOOD PRESSURE AND ROS; HOWEVER, THE EXACT MECHANISMS ARE NOT CLEAR. WHILE SEVERAL STUDIES HAVE UNDERLINED THE ROLE OF EPIGENETICS IN RENAL INFLAMMATION AND DYSFUNCTION, THE MECHANISMS THROUGH WHICH EPIGENETIC REGULATORS PLAY A ROLE IN HYPERTENSION ARE NOT WELL DEFINED. IN THIS STUDY, WE SOUGHT TO IDENTIFY WHETHER MICRORNAS ARE DYSREGULATED IN RESPONSE TO ANGIOTENSIN II (ANG II)-INDUCED HYPERTENSION IN THE KIDNEY AND WHETHER A H(2)S DONOR, GYY4137, COULD REVERSE THE MICRORNA ALTERATION AND KIDNEY FUNCTION. WILD-TYPE (C57BL/6J) MICE WERE TREATED WITHOUT OR WITH ANG II AND GYY4137 FOR 4 WK. BLOOD PRESSURE, RENAL BLOOD FLOW, AND RESISTIVE INDEX (RI) WERE MEASURED. MICRORNA MICROARRAYS WERE CONDUCTED AND SUBSEQUENT TARGET PREDICTION REVEALED GENES ASSOCIATED WITH A PROINFLAMMATORY RESPONSE. ANG II TREATMENT SIGNIFICANTLY INCREASED BLOOD PRESSURE, DECREASED BLOOD FLOW IN THE RENAL CORTEX, INCREASED RI, AND REDUCED RENAL FUNCTION. THESE EFFECTS WERE AMELIORATED IN MICE TREATED WITH GYY4137. MICROARRAY ANALYSIS REVEALED DOWNREGULATION OF MIR-129 IN ANG II-TREATED MICE AND UPREGULATION AFTER GYY4137 TREATMENT. QUANTITATION OF PROTEINS INVOLVED IN THE INFLAMMATORY RESPONSE AND DNA METHYLATION REVEALED UPREGULATION OF IL-17A AND DNA METHYLTRANSFERASE 3A, WHEREAS H(2)S PRODUCTION ENZYMES AND ANTI-INFLAMMATORY IL-10 WERE REDUCED. TAKEN TOGETHER, OUR DATA SUGGEST THAT DOWNREGULATION OF MIR-129 PLAYS A SIGNIFICANT ROLE IN ANG II-INDUCED RENAL INFLAMMATION AND FUNCTIONAL OUTCOMES AND THAT GYY4137 IMPROVES RENAL FUNCTION BY REVERSING MIR-129 EXPRESSION.NEW & NOTEWORTHY WE INVESTIGATED EPIGENETIC CHANGES THAT OCCUR IN THE HYPERTENSIVE KIDNEY AND HOW H(2)S SUPPLEMENTATION REVERSES ADVERSE EFFECTS. INFLAMMATION, ABERRANT METHYLATION, AND DYSFUNCTION WERE OBSERVED IN THE HYPERTENSIVE KIDNEY, AND THESE EFFECTS WERE ALLEVIATED WITH H(2)S SUPPLEMENTATION. WE IDENTIFY MIR-129 AS A POTENTIAL REGULATOR OF BLOOD PRESSURE AND H(2)S REGULATION. 2017 12 187 26 ACE2 EXPRESSION IS INCREASED IN THE LUNGS OF PATIENTS WITH COMORBIDITIES ASSOCIATED WITH SEVERE COVID-19. THE PANDEMIC CAUSED BY THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) HAS RESULTED IN SEVERAL THOUSAND DEATHS WORLDWIDE IN JUST A FEW MONTHS. PATIENTS WHO DIED FROM CORONAVIRUS DISEASE 2019 (COVID-19) OFTEN HAD COMORBIDITIES, SUCH AS HYPERTENSION, DIABETES, AND CHRONIC OBSTRUCTIVE LUNG DISEASE. THE ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) WAS IDENTIFIED AS A CRUCIAL FACTOR THAT FACILITATES SARS-COV2 TO BIND AND ENTER HOST CELLS. TO DATE, NO STUDY HAS ASSESSED THE ACE2 EXPRESSION IN THE LUNGS OF PATIENTS WITH THESE DISEASES. HERE, WE ANALYZED OVER 700 LUNG TRANSCRIPTOME SAMPLES OF PATIENTS WITH COMORBIDITIES ASSOCIATED WITH SEVERE COVID-19 AND FOUND THAT ACE2 WAS HIGHLY EXPRESSED IN THESE PATIENTS, COMPARED TO CONTROL INDIVIDUALS. THIS FINDING SUGGESTS THAT PATIENTS WITH SUCH COMORBIDITIES MAY HAVE HIGHER CHANCES OF DEVELOPING SEVERE COVID-19. WE ALSO FOUND OTHER GENES, SUCH AS RAB1A, THAT CAN BE IMPORTANT FOR SARS-COV-2 INFECTION IN THE LUNG. CORRELATION AND NETWORK ANALYSES REVEALED MANY POTENTIAL REGULATORS OF ACE2 IN THE HUMAN LUNG, INCLUDING GENES RELATED TO HISTONE MODIFICATIONS, SUCH AS HAT1, HDAC2, AND KDM5B. IN FACT, EPIGENETIC MARKS FOUND IN ACE2 LOCUS WERE COMPATIBLE TO WITH THOSE PROMOTED BY KDM5B. OUR SYSTEMS BIOLOGY APPROACH OFFERS A POSSIBLE EXPLANATION FOR INCREASE OF COVID-19 SEVERITY IN PATIENTS WITH CERTAIN COMORBIDITIES. 2020 13 3889 27 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 14 307 26 ALBUMINURIA DOWNREGULATION OF THE ANTI-AGING FACTOR KLOTHO: THE MISSING LINK POTENTIALLY EXPLAINING THE ASSOCIATION OF PATHOLOGICAL ALBUMINURIA WITH PREMATURE DEATH. TEN PERCENT OF THE ADULT POPULATION HAS CHRONIC KIDNEY DISEASE (CKD), WHICH IS DIAGNOSED WHEN THE GLOMERULAR FILTRATION RATE (GFR) IS BELOW 60 ML/MIN PER 1.73 M(2) OR WHEN ALBUMINURIA IS ABOVE 30 MG/DAY. THE NUMERICAL THRESHOLDS WERE CHOSEN BECAUSE THEY ARE ASSOCIATED WITH AN INCREASED RISK OF CKD PROGRESSION OR PREMATURE DEATH WITHIN A WIDER SCENARIO OF ACCELERATED AGING. INDEED, CKD IS ONE OF THE FASTEST GROWING CAUSES OF DEATH WORLDWIDE. A DECREASED GFR IS ASSOCIATED WITH THE ACCUMULATION OF URAEMIC TOXINS THAT MAY PROMOTE TISSUE AND ORGAN DAMAGE. HOWEVER, CKD MAY BE DIAGNOSED WHEN THE GFR IS COMPLETELY NORMAL, AS LONG AS THERE IS PATHOLOGICAL ALBUMINURIA. A KEY UNANSWERED QUESTION TO STEM THE RISE OF CKD-ASSOCIATED DEATHS IS WHETHER THE ASSOCIATION BETWEEN ISOLATED ALBUMINURIA (WHEN THE GFR IS NORMAL) AND PREMATURE DEATH IS CAUSAL. THE RECENT DEMONSTRATION THAT ALBUMINURIA PER SE DIRECTLY SUPPRESSES THE PRODUCTION OF THE ANTI-AGING FACTOR KLOTHO BY KIDNEY TUBULAR CELLS MAY BE ONE OF THE FIRST STEPS TO ADDRESS THE CAUSALITY OF THE ALBUMINURIA-PREMATURE DEATH-ACCELERATED AGING ASSOCIATION. THIS HYPOTHESIS SHOULD BE TESTED IN INTERVENTIONAL STUDIES THAT SHOULD DRAW FROM TRANSLATIONAL SCIENCE ADVANCES. THUS, THE OBSERVATION THAT ALBUMINURIA DECREASES KLOTHO PRODUCTION THROUGH EPIGENETIC MECHANISMS IMPLIES THAT KLOTHO DOWNREGULATION MAY PERSIST AFTER THE CORRECTION OF ALBUMINURIA, AND INNOVATIVE THERAPEUTIC APPROACHES ARE NEEDED TO RESTORE KLOTHO PRODUCTION. ON THE BASIS OF RECENT LITERATURE, THESE MAY INCLUDE MANIPULATION OF NF-KAPPAB REGULATORS SUCH AS B CELL LYMPHOMA 3 PROTEIN (BCL-3), AND EPIGENETIC REGULATORS SUCH AS HISTONE DEACETYLASES, OR THE REPURPOSING OF DRUGS SUCH AS PENTOXIFYLLINE. 2020 15 5363 16 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 16 3466 23 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 17 1665 25 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 18 6575 16 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 19 4752 21 NOVEL ROLE OF GESTATIONAL HYDRALAZINE IN LIMITING MATERNAL AND DIETARY OBESITY-RELATED CHRONIC KIDNEY DISEASE. BACKGROUND: MATERNAL OBESITY IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD) IN OFFSPRING, UNDERPINNING THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PROGRAMMING OF ADULT CHRONIC DISEASE BY MATERNAL OBESITY, THEREFORE, DNA DEMETHYLATING AGENTS MAY MITIGATE OFFSPRING RISK OF DISEASE. IN RODENT MODELS, LOW-DOSE HYDRALAZINE HAS PREVIOUSLY BEEN SHOWN TO REDUCE RENAL FIBROSIS VIA DNA DEMETHYLATION. WE USED MOUSE MODELS OF MATERNAL OBESITY AND OFFSPRING OBESITY TO DETERMINE WHETHER ADMINISTRATION OF LOW-DOSE HYDRALAZINE DURING GESTATION CAN PREVENT FETAL PROGRAMMING OF CKD IN OFFSPRING. METHODS: FEMALE C57BL/6 MICE RECEIVED HIGH FAT DIET (HFD) OR CHOW PRIOR TO MATING, DURING GESTATION AND LACTATION. DURING GESTATION, DAMS RECEIVED SUBCUTANEOUS HYDRALAZINE (5 MG/KG) OR SALINE THRICE-WEEKLY. MALE OFFSPRING WEANED TO HFD OR CHOW, WHICH CONTINUED UNTIL ENDPOINT AT 32 WEEKS. BIOMETRIC AND METABOLIC PARAMETERS, RENAL GLOBAL DNA METHYLATION, RENAL FUNCTIONAL AND STRUCTURAL CHANGES, AND RENAL MARKERS OF FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED AT ENDPOINT. RESULTS: OFFSPRING EXPOSED TO MATERNAL OBESITY OR DIET-INDUCED OBESITY HAD SIGNIFICANTLY INCREASED RENAL GLOBAL DNA METHYLATION, TOGETHER WITH OTHER ADVERSE RENAL EFFECTS INCLUDING ALBUMINURIA, GLOMERULOSCLEROSIS, RENAL FIBROSIS, AND OXIDATIVE STRESS. OFFSPRING EXPOSED TO GESTATIONAL HYDRALAZINE HAD SIGNIFICANTLY REDUCED RENAL GLOBAL DNA METHYLATION. IN OBESE OFFSPRING OF OBESE MOTHERS, GESTATIONAL HYDRALAZINE SIGNIFICANTLY DECREASED ALBUMINURIA, GLOMERULOSCLEROSIS, AND SERUM CREATININE. OBESE OFFSPRING OF HYDRALAZINE-TREATED LEAN MOTHERS DISPLAYED REDUCED MARKERS OF RENAL FIBROSIS AND OXIDATIVE STRESS. CONCLUSION: GESTATIONAL HYDRALAZINE DECREASED RENAL GLOBAL DNA METHYLATION AND EXERTED RENOPROTECTIVE EFFECTS IN OFFSPRING. THIS SUPPORTS A POTENTIAL THERAPEUTIC EFFECT OF HYDRALAZINE IN PREVENTING MATERNAL OBESITY OR DIETARY OBESITY-RELATED CKD, THROUGH AN EPIGENETIC MECHANISM. 2021 20 5994 30 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