1 4170 127 MEETING REPORT: ISN FOREFRONTS IN NEPHROLOGY ON ENDOTHELIAL BIOLOGY AND RENAL DISEASE: FROM BENCH TO PREVENTION. THIS ISN-SPONSORED FOREFRONT IN NEPHROLOGY MEETING, WHICH HAS BROUGHT TOGETHER 120 SCIENTISTS FROM 21 COUNTRIES, HAS BEEN CONCERNED WITH VARIOUS ASPECTS OF ENDOTHELIAL FUNCTION AND DYSFUNCTION AND THEIR CONTRIBUTION TO PROGRESSION OF CHRONIC KIDNEY DISEASE AND/OR ITS CARDIOVASCULAR COMPLICATIONS. THE FOLLOWING THEMES WERE DISCUSSED IN GREAT DEPTH: (1) PHENOTYPICAL CHANGES IN THE VASCULAR ENDOTHELIUM - PERMEABILITY, SENESCENCE, AND APOPTOSIS; (2) REGULATION OF ENDOTHELIAL NITRIC OXIDE (NO) SYNTHASE FUNCTION - CAVEOLAR AND SHEAR STRESS MECHANISMS, EPIGENETIC REGULATION, S-NITROSYLATION, AND RHO-KINASE REGULATION; (3) OXIDATIVE STRESS AND HYPOXIA-INDUCED CHANGES; (4) ORGANELLAR DYSFUNCTION - LYSOSOMES, MITOCHONDRIA, AND ENDOPLASMIC RETICULUM; (5) NO-INDEPENDENT MECHANISMS OF VASOMOTION - EPOXIDES, HEME OXYGENASE-1 AND CARBON MONOXIDE, THROMBOXANE, TUMOR NECROSIS FACTOR-ALPHA, AND URIC ACID; (6) ENDOTHELIAL CROSSTALK WITH PODOCYTES, MONOCYTES, SMOOTH MUSCLE CELLS, AND PLATELETS; (7) CANDIDATE CLINICAL BIOMARKERS OF ENDOTHELIAL DYSFUNCTION - FUNCTIONAL TESTING OF MACRO- AND MICRO-VASCULAR FUNCTIONS, SURROGATE MARKERS, CIRCULATING DETACHED ENDOTHELIAL CELLS, AND ENDOTHELIAL PRECURSOR CELLS; AND CULMINATED IN ROUND TABLE DISCUSSION ON THE DIAGNOSIS OF ENDOTHELIAL DYSFUNCTION AND ITS TREATMENT OPTIONS. IN CONCLUSION, THIS MEETING HAS FOCUSED ON SEVERAL KEY PROBLEMS OF ENDOTHELIAL CELL PATHOBIOLOGY RELEVANT TO CHRONIC KIDNEY DISEASE. 2006 2 3519 23 IGF-1 SIGNALING IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION: ROLE OF EPIGENETIC REGULATION. PULMONARY HYPERTENSION IS A FATAL DISEASE CHARACTERIZED BY A PROGRESSIVE INCREASE IN PULMONARY ARTERY PRESSURE ACCOMPANIED BY PULMONARY VASCULAR REMODELING AND INCREASED VASOMOTOR TONE. ALTHOUGH SOME BIOLOGICAL PATHWAYS HAVE BEEN IDENTIFIED IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH), LITTLE IS KNOWN REGARDING THE ROLE OF GROWTH FACTORS IN THE PATHOGENESIS OF PH IN NEONATES. IN THIS STUDY, USING A MODEL OF HYPOXIA-INDUCED PH IN NEONATAL MICE, WE DEMONSTRATE THAT THE GROWTH FACTOR INSULIN-LIKE GROWTH FACTOR-1 (IGF-1), A POTENT ACTIVATOR OF THE AKT SIGNALING PATHWAY, IS INVOLVED IN NEONATAL PH. AFTER EXPOSURE TO HYPOXIA, IGF-1 SIGNALING IS ACTIVATED IN PULMONARY ENDOTHELIAL AND SMOOTH MUSCLE CELLS IN VITRO, AND THE IGF-1 DOWNSTREAM SIGNAL PAKT(S473) IS UPREGULATED IN LUNGS OF NEONATAL MICE. WE FOUND THAT IGF-1 REGULATES ET-1 EXPRESSION IN PULMONARY ENDOTHELIAL CELLS AND THAT IGF-1 EXPRESSION IS REGULATED BY HISTONE DEACETYLASES (HDACS). IN ADDITION, THERE IS A DIFFERENTIAL CYTOSINE METHYLATION SITE IN THE IGF-1 PROMOTER REGION IN RESPONSE TO NEONATAL HYPOXIA. MOREOVER, INHIBITION OF HDACS WITH APICIDIN DECREASES NEONATAL HYPOXIA-INDUCED GLOBAL DNA METHYLATION LEVELS IN LUNGS AND SPECIFIC CYTOSINE METHYLATION LEVELS AROUND THE PULMONARY IGF-1 PROMOTER REGION. FINALLY, HDAC INHIBITION WITH APICIDIN REDUCES CHRONIC HYPOXIA-INDUCED ACTIVATION OF IGF-1/PAKT SIGNALING IN LUNGS AND ATTENUATES RIGHT VENTRICULAR HYPERTROPHY AND PULMONARY VASCULAR REMODELING. TAKEN TOGETHER, WE CONCLUDE THAT IGF-1, WHICH IS EPIGENETICALLY REGULATED, IS INVOLVED IN THE PATHOGENESIS OF PULMONARY HYPERTENSION IN NEONATAL MICE. THIS STUDY IMPLICATES A NOVEL HDAC/IGF-1 EPIGENETIC PATHWAY IN THE REGULATION OF HYPOXIA-INDUCED PH AND WARRANTS FURTHER STUDY OF THE ROLE OF IGF-1 IN NEONATAL PULMONARY HYPERTENSIVE DISEASE. 2015 3 5053 23 PHARMACOLOGY OF PULMONARY ARTERIAL HYPERTENSION: AN OVERVIEW OF CURRENT AND EMERGING THERAPIES. PULMONARY ARTERIAL HYPERTENSION IS A RARE AND DEVASTATING DISEASE CHARACTERIZED BY AN ABNORMAL CHRONIC INCREASE IN PULMONARY ARTERIAL PRESSURE ABOVE 20 MMHG AT REST, WITH A POOR PROGNOSIS IF NOT TREATED. CURRENTLY, THERE IS NOT A SINGLE FULLY EFFECTIVE THERAPY, EVEN THOUGH A DOZEN OF DRUGS HAVE BEEN DEVELOPED IN THE LAST DECADES. PULMONARY ARTERIAL HYPERTENSION IS A MULTIFACTORIAL DISEASE, MEANING THAT SEVERAL MOLECULAR MECHANISMS ARE IMPLICATED IN ITS PATHOLOGY. THE MAIN MOLECULAR PATHWAYS REGULATING THE PULMONARY VASOMOTOR TONE-ENDOTHELIN, NITRIC OXIDE, AND PROSTACYCLIN-ARE THE MOST BIOLOGICALLY AND THERAPEUTICALLY EXPLORED TO DATE. HOWEVER, DRUGS TARGETING THESE PATHWAYS HAVE ALREADY FOUND THEIR LIMITATIONS. IN THE LAST YEARS, TRANSLATIONAL RESEARCH AND CLINICAL TRIALS HAVE MADE A STRONG EFFORT IN SUGGESTING AND TESTING NOVEL THERAPEUTIC STRATEGIES FOR THIS DISEASE. THESE APPROACHES INVOLVE TARGETING THE MAIN MOLECULAR PATHWAYS WITH NOVEL DRUGS, DRUG REPURPOSING FOR NOVEL TARGETS, AND ALSO USING COMBINATORIAL THERAPIES. IN THIS REVIEW, WE SUMMARIZE CURRENT STRATEGIES AND DRUGS TARGETING THE ENDOTHELIN, NITRIC OXIDE, AND PROSTACYCLIN PATHWAYS, AS WELL AS, THE EMERGING NEW DRUGS PROPOSED TO COPE WITH VASCULAR REMODELLING, METABOLIC SWITCH, PERIVASCULAR INFLAMMATION, EPIGENETIC MODIFICATIONS, ESTROGEN DEREGULATION, SEROTONIN, AND OTHER NEUROHUMORAL MECHANISMS CHARACTERISTIC OF THIS DISEASE. NOWADAYS, PULMONARY ARTERIAL HYPERTENSION REMAINS AN INCURABLE DISEASE; HOWEVER, THE INCOMING NEW KNOWLEDGE MAKES US BELIEVE THAT NEW PROMISING THERAPIES ARE COMING TO THE CLINICAL ARENA SOON. 2020 4 1644 18 DOES THE ENVIRONMENT AFFECT MENOPAUSE? A REVIEW OF THE EFFECTS OF ENDOCRINE DISRUPTING CHEMICALS ON MENOPAUSE. ENDOCRINE DISRUPTING CHEMICALS ARE WIDELY DISTRIBUTED IN OUR ENVIRONMENT. HUMANS ARE EXPOSED TO THESE COMPOUNDS NOT ONLY THROUGH THEIR OCCUPATIONS, BUT ALSO THROUGH DIETARY CONSUMPTION AND EXPOSURE TO CONTAMINATED WATER, PERSONAL CARE PRODUCTS AND TEXTILES. CHEMICALS THAT ARE PERSISTENT IN THE BODY AND IN OUR ENVIRONMENT INCLUDE DIOXINS AND POLYCHLORINATED BIPHENYLS. NON-PERSISTENT CHEMICALS INCLUDING BISPHENOL A, PHTHALATES AND PARABENS ARE EQUALLY AS IMPORTANT BECAUSE THEY ARE UBIQUITOUS IN OUR ENVIRONMENT. HEAVY METALS, INCLUDING LEAD AND CADMIUM, CAN ALSO HAVE ENDOCRINE DISRUPTING PROPERTIES. ALTHOUGH DIFFICULT TO STUDY DUE TO THEIR VARIETY OF SOURCES OF EXPOSURES AND MECHANISMS OF ACTION, THESE CHEMICALS HAVE BEEN ASSOCIATED WITH EARLY MENOPAUSE, INCREASED FREQUENCY OF VASOMOTOR SYMPTOMS, ALTERED STEROID HORMONE LEVELS AND MARKERS OF DIMINISHED OVARIAN RESERVE. UNDERSTANDING THE IMPACTS OF THESE EXPOSURES IS IMPORTANT GIVEN THE POTENTIAL FOR EPIGENETIC MODIFICATION, WHICH CAN ALTER GENE FUNCTION AND RESULT IN MULTI-GENERATIONAL EFFECTS. THIS REVIEW SUMMARIZES FINDINGS IN HUMANS AND ANIMALS OR CELL-BASED MODELS FROM THE PAST DECADE OF RESEARCH. CONTINUED RESEARCH IS NEEDED TO ASSESS THE EFFECTS OF MIXTURES OF CHEMICALS, CHRONIC EXPOSURES AND NEW COMPOUNDS THAT ARE CONTINUOUSLY BEING DEVELOPED AS REPLACEMENTS FOR TOXIC CHEMICALS THAT ARE BEING PHASED OUT. 2023 5 2356 24 EPIGENETIC REGULATION OF PULMONARY ARTERIAL HYPERTENSION-INDUCED VASCULAR AND RIGHT VENTRICULAR REMODELING: NEW OPPORTUNITIES? PULMONARY ARTERY HYPERTENSION (PAH) IS A RARE CHRONIC DISEASE WITH HIGH IMPACT ON PATIENTS' QUALITY OF LIFE AND CURRENTLY NO AVAILABLE CURE. PAH IS CHARACTERIZED BY CONSTANT REMODELING OF THE PULMONARY ARTERY BY INCREASED PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS), FIBROBLASTS (FBS) AND ENDOTHELIAL CELLS (ECS). THIS REMODELING EVENTUALLY LEADS TO INCREASED PRESSURE IN THE RIGHT VENTRICLE (RV) AND SUBSEQUENT RIGHT VENTRICLE HYPERTROPHY (RVH) WHICH, WHEN LEFT UNTREATED, PROGRESSES INTO RIGHT VENTRICLE FAILURE (RVF). PAH CAN NOT ONLY ORIGINATE FROM HERITABLE MUTATIONS, BUT ALSO DEVELOP AS A CONSEQUENCE OF CONGENITAL HEART DISEASE, EXPOSURE TO DRUGS OR TOXINS, HIV, CONNECTIVE TISSUE DISEASE OR BE IDIOPATHIC. WHILE MUCH ATTENTION WAS DRAWN INTO INVESTIGATING AND DEVELOPING THERAPIES RELATED TO THE MOST WELL UNDERSTOOD SIGNALING PATHWAYS IN PAH, IN THE LAST DECADE, A SHIFT TOWARDS UNDERSTANDING THE EPIGENETIC MECHANISMS DRIVING THE DISEASE OCCURRED. IN THIS REVIEW, WE REFLECT ON THE DIFFERENT EPIGENETIC REGULATORY FACTORS THAT ARE ASSOCIATED WITH THE PATHOLOGY OF RV REMODELING, AND ON THEIR RELEVANCE TOWARDS A BETTER UNDERSTANDING OF THE DISEASE AND SUBSEQUENTLY, THE DEVELOPMENT OF NEW AND MORE EFFICIENT THERAPEUTIC STRATEGIES. 2020 6 4459 25 MOLECULAR MECHANISMS OF DIABETIC VASCULAR COMPLICATIONS. DIABETIC COMPLICATIONS ARE THE MAJOR CAUSES OF MORBIDITY AND MORTALITY IN PATIENTS WITH DIABETES. MICROVASCULAR COMPLICATIONS INCLUDE RETINOPATHY, NEPHROPATHY AND NEUROPATHY, WHICH ARE LEADING CAUSES OF BLINDNESS, END-STAGE RENAL DISEASE AND VARIOUS PAINFUL NEUROPATHIES; WHEREAS MACROVASCULAR COMPLICATIONS INVOLVE ATHEROSCLEROSIS RELATED DISEASES, SUCH AS CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE AND STROKE. DIABETIC COMPLICATIONS ARE THE RESULT OF INTERACTIONS AMONG SYSTEMIC METABOLIC CHANGES, SUCH AS HYPERGLYCEMIA, LOCAL TISSUE RESPONSES TO TOXIC METABOLITES FROM GLUCOSE METABOLISM, AND GENETIC AND EPIGENETIC MODULATORS. CHRONIC HYPERGLYCEMIA IS RECOGNIZED AS A MAJOR INITIATOR OF DIABETIC COMPLICATIONS. MULTIPLE MOLECULAR MECHANISMS HAVE BEEN PROPOSED TO MEDIATE HYPERGLYCEMIA'S ADVERSE EFFECTS ON VASCULAR TISSUES. THESE INCLUDE INCREASED POLYOL PATHWAY, ACTIVATION OF THE DIACYLGLYCEROL/PROTEIN KINASE C PATHWAY, INCREASED OXIDATIVE STRESS, OVERPRODUCTION AND ACTION OF ADVANCED GLYCATION END PRODUCTS, AND INCREASED HEXOSAMINE PATHWAY. IN ADDITION, THE ALTERATIONS OF SIGNAL TRANSDUCTION PATHWAYS INDUCED BY HYPERGLYCEMIA OR TOXIC METABOLITES CAN ALSO LEAD TO CELLULAR DYSFUNCTIONS AND DAMAGE VASCULAR TISSUES BY ALTERING GENE EXPRESSION AND PROTEIN FUNCTION. LESS STUDIED THAN THE TOXIC MECHANISMS, HYPERGLYCEMIA MIGHT ALSO INHIBIT THE ENDOGENOUS VASCULAR PROTECTIVE FACTORS SUCH AS INSULIN, VASCULAR ENDOTHELIAL GROWTH FACTOR, PLATELET-DERIVED GROWTH FACTOR AND ACTIVATED PROTEIN C, WHICH PLAY IMPORTANT ROLES IN MAINTAINING VASCULAR HOMEOSTASIS. THUS, EFFECTIVE THERAPIES FOR DIABETIC COMPLICATIONS NEED TO INHIBIT MECHANISMS INDUCED BY HYPERGLYCEMIA'S TOXIC EFFECTS AND ALSO ENHANCE THE ENDOGENOUS PROTECTIVE FACTORS. THE PRESENT REVIEW SUMMARIZES THESE MULTIPLE BIOCHEMICAL PATHWAYS ACTIVATED BY HYPERGLYCEMIA AND THE POTENTIAL THERAPEUTIC INTERVENTIONS THAT MIGHT PREVENT DIABETIC COMPLICATIONS. (J DIABETES INVEST, DOI: 10.1111/J.2040-1124.2010.00018.X, 2010). 2010 7 2378 22 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 8 6786 28 [CONSENSUS AND CONTROVERSY ON RESEARCH PROGRESS AND CLINICAL PRACTICE OF VASCULAR CALCIFICATION]. VASCULAR CALCIFICATION IS AN ACTIVE AND COMPLEX PATHOLOGICAL PROCESS REGULATED BY SEVERAL FACTORS. VASCULAR CALCIFICATION IS CLOSELY RELATED TO THE INCIDENCE AND MORTALITY OF THE CARDIOVASCULAR DISEASE, CHRONIC KIDNEY DISEASE AND OTHER DISEASES, WHICH AFFECTS MULTIPLE ORGANS AND SYSTEMS, THUS AFFECTING PEOPLE'S HEALTH. THEREFORE, MORE AND MORE ATTENTION IS PAID TO VASCULAR CALCIFICATION. AT PRESENT, THE PATHOGENESIS AND CLINICAL PRACTICE OF VASCULAR CALCIFICATION HAVE BEEN CONTINUOUSLY IMPROVED, WHICH MAINLY INCLUDES CALCIUM AND PHOSPHORUS IMBALANCE THEORY, VASCULAR SMOOTH MUSCLE CELL TRANSDIFFERENTIATION THEORY, BONE HOMEOSTASIS IMBALANCE THEORY, EPIGENETIC REGULATION THEORY, INFLAMMATION THEORY, EXTRACELLULAR MATRIX THEORY, NEW CELL FATE THEORY AND SO ON. HOWEVER, THERE ARE STILL MANY UNSOLVED PROBLEMS. SINCE THE OCCURRENCE AND DEVELOPMENT OF VASCULAR CALCIFICATION AFFECT MULTIPLE ORGANS AND SYSTEMS, THIS EXPERT CONSENSUS GATHERED CLINICIANS AND BASIC RESEARCH EXPERTS ENGAGED IN THE STUDY OF VASCULAR CALCIFICATION IN ORDER TO SUMMARIZE THE PROGRESS OF VARIOUS DISCIPLINES RELATED TO VASCULAR CALCIFICATION IN RECENT YEARS. THE PURPOSE OF THIS CONSENSUS IS TO SYSTEMATICALLY SUMMARIZE THE LATEST RESEARCH PROGRESS, TREATMENT CONSENSUS AND CONTROVERSY OF VASCULAR CALCIFICATION FROM THE ASPECTS OF EPIDEMIOLOGY, PATHOGENESIS, PREVENTION AND TREATMENT, SO AS TO PROVIDE THEORETICAL BASIS AND CLINICAL ENLIGHTENMENT FOR IN-DEPTH RESEARCH IN THIS FIELD. 2022 9 6699 25 VASCULAR CALCIFICATION IN CKD: NEW INSIGHTS INTO ITS MECHANISMS. VASCULAR CALCIFICATION (VC) IS A COMMON COMPLICATION OF CHRONIC KIDNEY DISEASE (CKD) AND CONTRIBUTES TO AN INCREASED RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. HOWEVER, EFFECTIVE THERAPIES ARE STILL UNAVAILABLE AT PRESENT. IT HAS BEEN WELL ESTABLISHED THAT VC ASSOCIATED WITH CKD IS NOT A PASSIVE PROCESS OF CALCIUM PHOSPHATE DEPOSITION, BUT AN ACTIVELY REGULATED AND CELL-MEDIATED PROCESS THAT SHARES MANY SIMILARITIES WITH BONE FORMATION. ADDITIONALLY, NUMEROUS STUDIES HAVE SUGGESTED THAT CKD PATIENTS HAVE SPECIFIC RISK FACTORS AND CONTRIBUTORS TO THE DEVELOPMENT OF VC, SUCH AS HYPERPHOSPHATEMIA, UREMIC TOXINS, OXIDATIVE STRESS AND INFLAMMATION. ALTHOUGH RESEARCH EFFORTS IN THE PAST DECADE HAVE GREATLY IMPROVED OUR KNOWLEDGE OF THE MULTIPLE FACTORS AND MECHANISMS INVOLVED IN CKD-RELATED VC, MANY QUESTIONS REMAIN UNANSWERED. MOREOVER, STUDIES FROM THE PAST DECADE HAVE DEMONSTRATED THAT EPIGENETIC MODIFICATIONS ABNORMALITIES, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NONCODING RNAS, PLAY AN IMPORTANT ROLE IN THE REGULATION OF VC. THIS REVIEW SEEKS TO PROVIDE AN OVERVIEW OF THE PATHOPHYSIOLOGICAL AND MOLECULAR MECHANISMS OF VC ASSOCIATED WITH CKD, MAINLY FOCUSING ON THE INVOLVEMENT OF EPIGENETIC MODIFICATIONS IN THE INITIATION AND PROGRESSION OF UREMIC VC, WITH THE AIM TO DEVELOP PROMISING THERAPIES FOR CKD-RELATED CARDIOVASCULAR EVENTS IN THE FUTURE. 2023 10 1872 26 EMERGING ROLE OF LONG NON-CODING RNAS IN ENDOTHELIAL DYSFUNCTION AND THEIR MOLECULAR MECHANISMS. LONG NON-CODING RNAS (LNCRNAS) ARE THE NOVEL CLASS OF TRANSCRIPTS INVOLVED IN TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL REGULATION OF PHYSIOLOGY AND THE PATHOLOGY OF DISEASES. STUDIES HAVE EVIDENCED THAT THE IMPAIRMENT OF ENDOTHELIUM IS A CRITICAL EVENT IN THE PATHOGENESIS OF ATHEROSCLEROSIS AND ITS COMPLICATIONS. ENDOTHELIAL DYSFUNCTION IS CHARACTERIZED BY AN IMBALANCE IN VASODILATION AND VASOCONSTRICTION, OXIDATIVE STRESS, PROINFLAMMATORY FACTORS, AND NITRIC OXIDE BIOAVAILABILITY. DISRUPTION OF THE ENDOTHELIAL BARRIER PERMEABILITY, THE FIRST STEP IN DEVELOPING ATHEROSCLEROTIC LESIONS IS A CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION. THOUGH SEVERAL FACTORS INTERFERE WITH THE NORMAL FUNCTIONING OF THE ENDOTHELIUM, INTRINSIC EPIGENETIC MECHANISMS GOVERNING ENDOTHELIAL FUNCTION ARE REGULATED BY LNCRNAS AND PERTURBATIONS CONTRIBUTE TO THE PATHOGENESIS OF THE DISEASE. THIS REVIEW COMPREHENSIVELY ADDRESSES THE BIOGENESIS OF LNCRNA AND MOLECULAR MECHANISMS UNDERLYING AND REGULATION IN ENDOTHELIAL FUNCTION. AN INSIGHT CORRELATING LNCRNAS AND ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES CAN POSITIVELY IMPACT THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS IN ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES AND TREATMENT STRATEGIES. 2022 11 1895 31 ENDOTHELIAL DYSFUNCTION IN INDIVIDUALS BORN AFTER FETAL GROWTH RESTRICTION: CARDIOVASCULAR AND RENAL CONSEQUENCES AND PREVENTIVE APPROACHES. INDIVIDUALS BORN AFTER INTRAUTERINE GROWTH RESTRICTION (IUGR) HAVE AN INCREASED RISK OF PERINATAL MORBIDITY/MORTALITY, AND THOSE WHO SURVIVE FACE LONG-TERM CONSEQUENCES SUCH AS CARDIOVASCULAR-RELATED DISEASES, INCLUDING SYSTEMIC HYPERTENSION, ATHEROSCLEROSIS, CORONARY HEART DISEASE AND CHRONIC KIDNEY DISEASE. IN ADDITION TO THE DEMONSTRATED LONG-TERM EFFECTS OF DECREASED NEPHRON ENDOWMENT AND HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, INDIVIDUALS BORN AFTER IUGR ALSO EXHIBIT EARLY ALTERATIONS IN VASCULAR STRUCTURE AND FUNCTION, WHICH HAVE BEEN IDENTIFIED AS KEY FACTORS OF THE DEVELOPMENT OF CARDIOVASCULAR-RELATED DISEASES. THE ENDOTHELIUM PLAYS A MAJOR ROLE IN MAINTAINING VASCULAR FUNCTION AND HOMEOSTASIS. THEREFORE, IT IS NOT SURPRISING THAT IMPAIRED ENDOTHELIAL FUNCTION CAN LEAD TO THE LONG-TERM DEVELOPMENT OF VASCULAR-RELATED DISEASES. ENDOTHELIAL DYSFUNCTION, PARTICULARLY IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION AND VASCULAR REMODELING, INVOLVES DECREASED NITRIC OXIDE (NO) BIOAVAILABILITY, IMPAIRED ENDOTHELIAL NO SYNTHASE FUNCTIONALITY, INCREASED OXIDATIVE STRESS, ENDOTHELIAL PROGENITOR CELLS DYSFUNCTION AND ACCELERATED VASCULAR SENESCENCE. PREVENTIVE APPROACHES SUCH AS BREASTFEEDING, SUPPLEMENTATION WITH FOLATE, VITAMINS, ANTIOXIDANTS, L-CITRULLINE, L-ARGININE AND TREATMENT WITH NO MODULATORS REPRESENT PROMISING STRATEGIES FOR IMPROVING ENDOTHELIAL FUNCTION, MITIGATING LONG-TERM OUTCOMES AND POSSIBLY PREVENTING IUGR OF VASCULAR ORIGIN. MOREOVER, THE IDENTIFICATION OF EARLY BIOMARKERS OF ENDOTHELIAL DYSFUNCTION, ESPECIALLY EPIGENETIC BIOMARKERS, COULD ALLOW EARLY SCREENING AND FOLLOW-UP OF INDIVIDUALS AT RISK OF DEVELOPING CARDIOVASCULAR AND RENAL DISEASES, THUS CONTRIBUTING TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES TO AVERT THE LONG-TERM EFFECTS OF ENDOTHELIAL DYSFUNCTION IN INFANTS BORN AFTER IUGR. 2017 12 4978 19 PATHOPHYSIOLOGY AND NEW ADVANCES IN PULMONARY HYPERTENSION. PULMONARY HYPERTENSION IS A PROGRESSIVE AND OFTEN FATAL CARDIOPULMONARY CONDITION CHARACTERISED BY INCREASED PULMONARY ARTERIAL PRESSURE, STRUCTURAL CHANGES IN THE PULMONARY CIRCULATION, AND THE FORMATION OF VASO-OCCLUSIVE LESIONS. THESE CHANGES LEAD TO INCREASED RIGHT VENTRICULAR AFTERLOAD, WHICH OFTEN PROGRESSES TO MALADAPTIVE RIGHT VENTRICULAR REMODELLING AND EVENTUALLY DEATH. PULMONARY ARTERIAL HYPERTENSION REPRESENTS ONE OF THE MOST SEVERE AND BEST STUDIED TYPES OF PULMONARY HYPERTENSION AND IS CONSISTENTLY TARGETED BY DRUG TREATMENTS. THE UNDERLYING MOLECULAR PATHOGENESIS OF PULMONARY HYPERTENSION IS A COMPLEX AND MULTIFACTORIAL PROCESS, BUT CAN BE CHARACTERISED BY SEVERAL HALLMARKS: INFLAMMATION, IMPAIRED ANGIOGENESIS, METABOLIC ALTERATIONS, GENETIC OR EPIGENETIC ABNORMALITIES, INFLUENCE OF SEX AND SEX HORMONES, AND ABNORMALITIES IN THE RIGHT VENTRICLE. CURRENT TREATMENTS FOR PULMONARY ARTERIAL HYPERTENSION AND SOME OTHER TYPES OF PULMONARY HYPERTENSION TARGET PATHWAYS INVOLVED IN THE CONTROL OF PULMONARY VASCULAR TONE AND PROLIFERATION; HOWEVER, THESE TREATMENTS HAVE LIMITED EFFICACY ON PATIENT OUTCOMES. THIS REVIEW DESCRIBES KEY FEATURES OF PULMONARY HYPERTENSION, DISCUSSES CURRENT AND EMERGING THERAPEUTIC INTERVENTIONS, AND POINTS TO FUTURE DIRECTIONS FOR RESEARCH AND PATIENT CARE. BECAUSE MOST PROGRESS IN THE SPECIALTY HAS BEEN MADE IN PULMONARY ARTERIAL HYPERTENSION, THIS REVIEW FOCUSES ON THIS TYPE OF PULMONARY HYPERTENSION. THE REVIEW HIGHLIGHTS KEY PATHOPHYSIOLOGICAL CONCEPTS AND EMERGING THERAPEUTIC DIRECTIONS, TARGETING INFLAMMATION, CELLULAR METABOLISM, GENETICS AND EPIGENETICS, SEX HORMONE SIGNALLING, BONE MORPHOGENETIC PROTEIN SIGNALLING, AND INHIBITION OF TYROSINE KINASE RECEPTORS. 2023 13 1898 22 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 14 4433 19 MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS OF DIABETES MELLITUS - A COMPREHENSIVE REVIEW. DIABETES IS A CHRONIC DISEASE, CHARACTERIZED BY HYPERGLYCEMIA, WHICH REFERS TO THE ELEVATED LEVELS OF GLUCOSE IN THE BLOOD, DUE TO THE INABILITY OF THE BODY TO PRODUCE OR USE INSULIN EFFECTIVELY. CHRONIC HYPERGLYCEMIA LEVELS LEAD TO MACROVASCULAR AND MICROVASCULAR COMPLICATIONS. THE MACROVASCULAR COMPLICATIONS CONSIST OF PERIPHERAL ARTERY DISEASE (PAD), CARDIOVASCULAR DISEASES (CVD) AND CEREBROVASCULAR DISEASES, WHILE THE MICROVASCULAR COMPLICATIONS COMPRISE OF DIABETIC MICROANGIOPATHY, DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY AND DIABETIC NEUROPATHY. VASCULAR ENDOTHELIAL DYSFUNCTION PLAYS A CRUCIAL ROLE IN MEDIATING BOTH MACROVASCULAR AND MICROVASCULAR COMPLICATIONS UNDER HYPERGLYCEMIC CONDITIONS. IN DIABETIC MICROVASCULATURE, THE INTRACELLULAR HYPERGLYCEMIA CAUSES DAMAGE TO THE VASCULAR ENDOTHELIUM THROUGH - (I) ACTIVATION OF FOUR BIOCHEMICAL PATHWAYS, NAMELY THE POLYOL PATHWAY, PROTEIN KINASE C (PKC) PATHWAY, ADVANCED GLYCATION END PRODUCTS (AGE) PATHWAY AND HEXOSAMINE PATHWAY, ALL OF WHICH COMMUTES GLUCOSE AND ITS INTERMEDIATES LEADING TO OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DYSREGULATION OF GROWTH FACTORS AND CYTOKINES, (III) EPIGENETIC CHANGES WHICH CONCERN THE CHANGES IN DNA AS A RESPONSE TO INTRACELLULAR CHANGES, AND (IV) ABNORMALITIES IN NON-CODING RNAS, SPECIFICALLY MICRORNAS. THIS REVIEW WILL FOCUS ON GAINING AN UNDERSTANDING OF THE MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS IN DIABETES MELLITUS, TO INCREASE OUR UNDERSTANDING TOWARDS THE DEVELOPMENT OF NEW MECHANISTIC THERAPEUTIC STRATEGIES TO PREVENT OR TREAT DIABETES-INDUCED VASCULAR COMPLICATIONS. 2020 15 3467 22 HYPOXIA, HIF, AND ASSOCIATED SIGNALING NETWORKS IN CHRONIC KIDNEY DISEASE. THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD) IS COMPLEX AND APPARENTLY MULTIFACTORIAL. HYPOXIA OR DECREASE IN OXYGEN SUPPLY IN KIDNEY TISSUES HAS BEEN IMPLICATED IN CKD. HYPOXIA INDUCIBLE FACTORS (HIF) ARE A SMALL FAMILY OF TRANSCRIPTION FACTORS THAT ARE MAINLY RESPONSIVE TO HYPOXIA AND MEDIATE HYPOXIC RESPONSE. HIF PLAYS A CRITICAL ROLE IN RENAL FIBROSIS DURING CKD THROUGH THE MODULATION OF GENE TRANSCRIPTION, CROSSTALK WITH MULTIPLE SIGNALING PATHWAYS, EPITHELIAL-MESENCHYMAL TRANSITION, AND EPIGENETIC REGULATION. MOREOVER, HIF ALSO CONTRIBUTES TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL CONDITIONS ASSOCIATED WITH CKD, SUCH AS ANEMIA, INFLAMMATION, ABERRANT ANGIOGENESIS, AND VASCULAR CALCIFICATION. TREATMENTS TARGETING HIF AND RELATED SIGNALING PATHWAYS FOR CKD THERAPY ARE BEING DEVELOPED WITH PROMISING CLINICAL BENEFITS, ESPECIALLY FOR ANEMIA. THIS REVIEW PRESENTS AN UPDATED ANALYSIS OF HYPOXIA RESPONSE, HIF, AND THEIR ASSOCIATED SIGNALING NETWORK INVOLVED IN THE PATHOGENESIS OF CKD. 2017 16 4415 30 MOLECULAR AND CELLULAR MECHANISMS THAT INDUCE ARTERIAL CALCIFICATION BY INDOXYL SULFATE AND P-CRESYL SULFATE. THE PROTEIN-BOUND UREMIC TOXINS, INDOXYL SULFATE (IS) AND P-CRESYL SULFATE (PCS), ARE CONSIDERED TO BE HARMFUL VASCULAR TOXINS. ARTERIAL MEDIA CALCIFICATION, OR THE DEPOSITION OF CALCIUM PHOSPHATE CRYSTALS IN THE ARTERIES, CONTRIBUTES SIGNIFICANTLY TO CARDIOVASCULAR COMPLICATIONS, INCLUDING LEFT VENTRICULAR HYPERTROPHY, HYPERTENSION, AND IMPAIRED CORONARY PERFUSION IN THE ELDERLY AND PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND DIABETES. RECENTLY, WE REPORTED THAT BOTH IS AND PCS TRIGGER MODERATE TO SEVERE CALCIFICATION IN THE AORTA AND PERIPHERAL VESSELS OF CKD RATS. THIS REVIEW DESCRIBES THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH THESE UREMIC TOXINS INDUCE ARTERIAL MEDIA CALCIFICATION. A COMPLEX INTERPLAY BETWEEN INFLAMMATION, COAGULATION, AND LIPID METABOLISM PATHWAYS, INFLUENCED BY EPIGENETIC FACTORS, IS CRUCIAL IN IS/PCS-INDUCED ARTERIAL MEDIA CALCIFICATION. HIGH LEVELS OF GLUCOSE ARE LINKED TO THESE EVENTS, SUGGESTING THAT A GOOD BALANCE BETWEEN GLUCOSE AND LIPID LEVELS MIGHT BE IMPORTANT. ON THE CELLULAR LEVEL, EFFECTS ON ENDOTHELIAL CELLS, WHICH ACT AS THE PRIMARY SENSORS OF CIRCULATING PATHOLOGICAL TRIGGERS, MIGHT BE AS IMPORTANT AS THOSE ON VASCULAR SMOOTH MUSCLE CELLS. ENDOTHELIAL DYSFUNCTION, PROVOKED BY IS AND PCS TRIGGERED OXIDATIVE STRESS, MAY BE CONSIDERED A KEY EVENT IN THE ONSET AND DEVELOPMENT OF ARTERIAL MEDIA CALCIFICATION. IN THIS REVIEW A NUMBER OF IMPORTANT OUTSTANDING QUESTIONS SUCH AS THE ROLE OF MIRNA'S, PHENOTYPIC SWITCHING OF BOTH ENDOTHELIAL AND VASCULAR SMOOTH MUSCLE CELLS AND NEW TYPES OF PROGRAMMED CELL DEATH IN ARTERIAL MEDIA CALCIFICATION RELATED TO PROTEIN-BOUND UREMIC TOXINS ARE PUT FORWARD AND DISCUSSED. 2020 17 6409 24 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019 18 4109 20 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 19 5826 28 STRESS SIGNAL NETWORK BETWEEN HYPOXIA AND ER STRESS IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY AN IRREVERSIBLE DECREASE IN KIDNEY FUNCTION AND INDUCTION OF VARIOUS METABOLIC DYSFUNCTIONS. ACCUMULATED FINDINGS REVEAL THAT CHRONIC HYPOXIC STRESS AND ENDOPLASMIC RETICULUM (ER) STRESS ARE INVOLVED IN A RANGE OF PATHOGENIC CONDITIONS, INCLUDING THE PROGRESSION OF CKD. BECAUSE OF THE PRESENCE OF AN ARTERIOVENOUS OXYGEN SHUNT, THE KIDNEY IS THOUGHT TO BE SUSCEPTIBLE TO HYPOXIA. CHRONIC KIDNEY HYPOXIA IS INDUCED BY A NUMBER OF PATHOGENIC CONDITIONS, INCLUDING RENAL ISCHEMIA, REDUCED PERITUBULAR CAPILLARY, AND TUBULOINTERSTITIAL FIBROSIS. THE ER IS AN ORGANELLE WHICH HELPS MAINTAIN THE QUALITY OF PROTEINS THROUGH THE UNFOLDED PROTEIN RESPONSE (UPR) PATHWAY, AND ER DYSFUNCTION ASSOCIATED WITH MALADAPTIVE UPR ACTIVATION IS NAMED ER STRESS. ER STRESS IS REPORTED TO BE RELATED TO SOME OF THE EFFECTS OF PATHOGENESIS IN KIDNEY, PARTICULARLY IN THE PODOCYTE SLIT DIAPHRAGM AND TUBULOINTERSTITIUM. FURTHERMORE, CHRONIC HYPOXIA MEDIATES ER STRESS IN BLOOD VESSEL ENDOTHELIAL CELLS AND TUBULOINTERSTITIUM VIA SEVERAL MECHANISMS, INCLUDING OXIDATIVE STRESS, EPIGENETIC ALTERATION, LIPID METABOLISM, AND THE AKT PATHWAY. IN SUMMARY, A GROWING CONSENSUS CONSIDERS THAT THESE STRESSES INTERACT VIA COMPLICATED STRESS SIGNAL NETWORKS, WHICH LEADS TO THE EXACERBATION OF CKD (FIGURE 1). THIS STRESS SIGNAL NETWORK MIGHT BE A TARGET FOR INTERVENTIONS AIMED AT AMELIORATING CKD. 2017 20 5048 27 PHARMACOLOGICAL APPROACHES IN EITHER INTERMITTENT OR PERMANENT HYPOXIA: A TALE OF TWO EXPOSURES. HYPOXIA INDUCES SEVERAL RESPONSES AT CARDIOVASCULAR, PULMONARY AND REPRODUCTIVE LEVELS, WHICH MAY LEAD TO CHRONIC DISEASES. THIS IS RELEVANT IN HUMAN POPULATIONS EXPOSED TO HIGH ALTITUDE (HA), IN EITHER CHRONIC CONTINUOUS (PERMANENT INHABITANTS) OR INTERMITTENT FASHION (HA WORKERS, TOURISTS AND MOUNTAINEERS). IN CHILE, IT IS ESTIMATED THAT 1.000.000 PEOPLE LIVE AT HIGHLANDS AND MORE THAN 55.000 WORK IN HA SHIFTS. INITIAL RESPONSES TO HYPOXIA ARE COMPENSATORY AND INDUCE ACTIVATION OF CARDIOPROTECTIVE MECHANISMS, SUCH AS THOSE SEEN UNDER INTERMITTENT HYPOBARIC (IH) HYPOXIA, EVENTS THAT COULD MEDIATE PRECONDITIONING. HOWEVER, WHENEVER HYPOXIA IS PROLONGED, THE CHRONIC ACTIVATION OF CELLULAR RESPONSES INDUCES LONG-LASTING MODIFICATIONS THAT MAY RESULT IN ACCLIMATIZATION OR PRODUCE MALADAPTIVE CHANGES WITH INCREASE IN CARDIOVASCULAR RISK. HA EXPOSURE DURING PREGNANCY INDUCES HYPOXIA AND OXIDATIVE STRESS, WHICH IN TURN MAY PROMOTE CELLULAR RESPONSES AND EPIGENETIC MODIFICATIONS RESULTING IN SEVERE IMPAIRMENT IN GROWTH AND DEVELOPMENT. SADLY, THIS CONDITION IS ACCOMPANIED WITH AN INCREASED FETAL AND NEONATAL MORBI-MORTALITY. FURTHER, DEVELOPMENTAL HYPOXIA MAY PROGRAM CARDIO-PULMONARY CIRCULATIONS LATER IN POSTNATAL LIFE, ENDING IN VASCULAR STRUCTURAL AND FUNCTIONAL ALTERATIONS WITH AUGMENTED RISK ON PULMONARY AND CARDIOVASCULAR FAILURE. ADDITIONALLY, PERMANENT HA INHABITANTS HAVE AUGMENTED RISK AND PREVALENCE OF CHRONIC HYPOXIC PULMONARY HYPERTENSION, RIGHT VENTRICULAR HYPERTROPHY AND CARDIOPULMONARY REMODELING. SIMILAR RESPONSES ARE SEEN IN ADULTS THAT ARE INTERMITTENTLY EXPOSED TO CHRONIC HYPOXIA (CH) SUCH AS SHIFT WORKERS IN HA AREAS. THE MECHANISMS INVOLVED DETERMINING THE IMMEDIATE, SHORT AND LONG-LASTING EFFECTS ARE STILL UNCLEAR. FOR SEVERAL YEARS, THE STUDY OF THE RESPONSES TO HYPOXIC INSULTS AND PHARMACOLOGICAL TARGETS HAS BEEN THE MOTIVATION OF OUR GROUP. THIS REVIEW DESCRIBES SOME OF THE MECHANISMS UNDERLYING HYPOXIC RESPONSES AND POTENTIAL THERAPEUTIC APPROACHES WITH ANTIOXIDANTS SUCH AS MELATONIN, ASCORBATE, OMEGA 3 (OMEGA3) OR COMPOUNDS THAT INCREASE THE NITRIC OXIDE (NO) BIOAVAILABILITY. 2015