1 3466 106 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 2 5826 33 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 3 2034 54 EPIGENETIC CHANGES IN THE ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. PREVIOUSLY ACUTE KIDNEY INJURY (AKI) HAD BEEN BELIEVED TO BE A TRANSIENT EVENT, AND RECOVERY FROM AKI HAD BEEN THOUGHT TO LEAD TO NO CONSEQUENCES. HOWEVER, RECENT EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT EVEN IF THERE IS COMPLETE RECOVERY OF THE KIDNEY FUNCTION, AKI CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD) AND EVENTUALLY IN END-STAGE KIDNEY DISEASE IN THE LONG TERM. TRANSITION OF AKI TO CKD IS MEDIATED BY MULTIPLE MECHANISMS, INCLUDING ABERRANT CELL CYCLE ARREST AND HYPOXIA. HYPOXIA OF THE KIDNEY IS INDUCED BY RAREFACTION OF THE PERITUBULAR CAPILLARIES AFTER AKI EPISODES, AND INDUCES INFLAMMATION AND FIBROSIS. IT SHOULD ALSO BE NOTED THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO HYPOXIA, AND EPIGENETIC CHANGES INDUCED BY HYPOXIA, CALLED "HYPOXIC MEMORY" CAN EXPLAIN THE AKI-TO-CKD TRANSITION IN THE LONG TERM AFTER COMPLETE RECOVERY FROM THE INITIAL AKI EPISODE. TARGETING HYPOXIA AND SUBSEQUENT EPIGENETIC CHANGES ARE PROMISING STRATEGIES TO BLOCK THE TRANSITION FROM AKI TO CKD. 2017 4 6647 39 UPDATE OF PERICYTES FUNCTION AND THEIR ROLES IN KIDNEY DISEASES. STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT INVOLVEMENT OF KIDNEY PERICYTES IN RENAL FIBROSIS. KIDNEY PERICYTES, CLASSIFIED AS INTERSTITIAL MESENCHYMAL CELLS, ARE EXTENSIVELY BRANCHED, COLLAGEN-PRODUCING CELLS THAT CLOSELY INTERACT WITH ENDOTHELIAL CELLS. THIS ARTICLE AIMS TO PROVIDE AN OVERVIEW OF THE RECENT ADVANCEMENTS IN UNDERSTANDING THE PHYSIOLOGICAL FUNCTIONS OF PERICYTES AND THEIR ROLES IN KIDNEY DISEASES. IN A HEALTHY KIDNEY, PERICYTES HAVE ESSENTIAL PHYSIOLOGICAL FUNCTION IN ANGIOGENESIS, ERYTHROPOIETIN (EPO) PRODUCTION, AND THE REGULATION OF RENAL BLOOD FLOW. NEVERTHELESS, PERICYTE-MYOFIBROBLAST TRANSITION HAS BEEN IDENTIFIED AS THE PRIMARY CAUSE OF DISEASE PROGRESSION IN ACUTE KIDNEY INJURY (AKI)-TO-CHRONIC KIDNEY DISEASE (CKD) CONTINUUM. OUR RECENT RESEARCH HAS DEMONSTRATED THAT HYPOXIA-INDUCIBLE FACTOR-2ALPHA (HIF-2ALPHA) REGULATES ERYTHROPOIETIN PRODUCTION IN PERICYTES. HOWEVER, THIS PRODUCTION IS REPRESSED BY EPO GENE HYPERMETHYLATION AND HIF-2ALPHA DOWNREGULATION WHICH WERE INDUCED BY TRANSFORMING GROWTH FACTOR-BETA1-ACTIVATED DNA METHYLTRANSFERASE AND ACTIVIN RECEPTOR-LIKE KINASE-5 SIGNALING PATHWAY DURING RENAL FIBROSIS, RESPECTIVELY. ADDITIONALLY, AKI INDUCES EPIGENETIC MODIFICATIONS IN PERICYTES, RENDERING THEM MORE PRONE TO EXTRACELLULAR MATRIX PRODUCTION, CELL MIGRATION AND PROLIFERATION, THEREBY CONTRIBUTING TO SUBSEQUENT CAPILLARY RAREFACTION AND RENAL FIBROSIS. FURTHER INVESTIGATION INTO THE SPECIFIC FUNCTIONS AND ROLES OF DIFFERENT SUBPOPULATIONS OF PERICYTES MAY CONTRIBUTE FOR THE DEVELOPMENT OF TARGETED THERAPIES AIMED AT ATTENUATING KIDNEY DISEASE AND MITIGATING THEIR ADVERSE EFFECTS. 2023 5 5054 30 PHARMACOPROTEOMICS REVEAL NOVEL PROTECTIVE ACTIVITY OF BROMODOMAIN CONTAINING 4 INHIBITORS ON VASCULAR HOMEOSTASIS IN TLR3-MEDIATED AIRWAY REMODELING. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. WE REPORT A SYSTEMS-LEVEL PHARMACOPROTEOMICS IN A STANDARDIZED MURINE MODEL OF TOLL-LIKE RECEPTOR TLR3-NFKAPPAB/RELA INNATE INFLAMMATION IN THE ABSENCE OR PRESENCE OF A HIGHLY SELECTIVE BRD4 INHIBITOR (ZL0454) OR NONSELECTIVE BROMODOMAIN AND EXTRATERMINAL DOMAIN INHIBITOR (JQ1). PROTEOMICS OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) SECRETOME AND EXOSOMAL PROTEINS FROM THIS MURINE MODEL REVEALED INCREASED, SELECTIVE, CAPILLARY LEAK ASSOCIATED WITH PERICYTE-MYOFIBROBLAST TRANSITION, A PHENOMENON BLOCKED BY BRD4 INHIBITORS. BALF PROTEOMICS ALSO SUGGESTED THAT ZL0454 BETTER REDUCED THE VASCULAR LEAKAGE AND EXTRACELLULAR MATRIX DEPOSITION THAN JQ1. A SIGNIFICANT SUBSET OF INFLAMMATION-MEDIATED REMODELING FACTORS WAS ALSO IDENTIFIED IN A MOUSE MODEL OF IDIOPATHIC PULMONARY FIBROSIS PRODUCED BY BLEOMYCIN. BALF EXOSOME ANALYSIS INDICATED THAT BRD4 INHIBITORS REDUCED THE INDUCTION OF EXOSOMES ENRICHED IN COAGULATION FACTORS WHOSE PRESENCE CORRELATED WITH INTERSTITIAL FIBRIN DEPOSITION. FINALLY, BALF SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR UPREGULATIONS OF ORM2, APCS, SPARCL1, FGA, AND FN1, SUGGESTING THEIR POTENTIAL AS BIOMARKERS FOR EARLY DETECTION OF AIRWAY REMODELING AND/OR MONITORING OF THERAPY RESPONSE. SIGNIFICANCE: REPETITIVE AND CHRONIC VIRAL UPPER RESPIRATORY TRACT INFECTIONS TRIGGER TOLL-LIKE RECEPTOR (TLR)3-NFKAPPAB/RELA MEDIATED AIRWAY REMODELING WHICH IS LINKED TO A PROGRESSIVE DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. OUR STUDY REVEALED THAT THE ACTIVATION OF (TLR)3-NFKAPPAB/RELA PATHWAY IN THE LUNG INDUCED AN ELEVATION IN COAGULATION, COMPLEMENT, AND PLATELET FACTORS, INDICATING THE INCREASED VASCULAR LEAK DURING AIRWAY REMODELING. THE MECHANISM OF VASCULAR LEAKAGE WAS CHRONIC INFLAMMATION-INDUCED PERICYTE-MYOFIBROBLAST TRANSITION, WHICH WAS BLOCKED BY BRD4 INHIBITORS. FINALLY, PROTEOMICS ANALYSIS OF THE BRONCHOALVEOLAR LAVAGE FLUID SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR FINDINGS THAT WE OBSERVED IN THE ANIMAL MODEL. 2019 6 4882 33 OVERVIEW OF THE CELLULAR AND MOLECULAR BASIS OF KIDNEY FIBROSIS. THE COMMON PATHOGENETIC PATHWAY OF PROGRESSIVE INJURY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS EPITOMIZED AS NORMAL KIDNEY PARENCHYMAL DESTRUCTION DUE TO SCARRING (FIBROSIS). UNDERSTANDING THE FUNDAMENTAL PATHWAYS THAT LEAD TO RENAL FIBROSIS IS ESSENTIAL IN ORDER TO DEVELOP BETTER THERAPEUTIC OPTIONS FOR HUMAN CKD. ALTHOUGH COMPLEX, FOUR CELLULAR RESPONSES ARE PIVOTAL. (1) AN INTERSTITIAL INFLAMMATORY RESPONSE THAT HAS MULTIPLE CONSEQUENCES-SOME HARMFUL AND OTHERS HEALING. (2) THE APPEARANCE OF A UNIQUE INTERSTITIAL CELL POPULATION OF MYOFIBROBLASTS, PRIMARILY DERIVED FROM KIDNEY STROMAL CELLS (FIBROBLASTS AND PERICYTES), THAT ARE THE PRIMARY SOURCE OF THE VARIOUS EXTRACELLULAR MATRIX PROTEINS THAT FORM INTERSTITIAL SCARS. (3) TUBULAR EPITHELIAL CELLS THAT HAVE VARIABLE AND TIME-DEPENDENT ROLES AS EARLY RESPONDERS TO INJURY AND LATER AS VICTIMS OF FIBROSIS DUE TO THE LOSS OF THEIR REGENERATIVE ABILITIES. (4) LOSS OF INTERSTITIAL CAPILLARY INTEGRITY THAT COMPROMISES OXYGEN DELIVERY AND LEADS TO A VICIOUS CASCADE OF HYPOXIA-OXIDANT STRESS THAT ACCENTUATES INJURY AND FIBROSIS. IN THE ABSENCE OF ADEQUATE ANGIOGENIC RESPONSES, A HEALTHY INTERSTITIAL CAPILLARY NETWORK IS NOT MAINTAINED. THE FIBROTIC 'SCAR' THAT TYPIFIES CKD IS AN INTERESTING CONSORTIUM OF MULTIFUNCTIONAL MACROMOLECULES THAT NOT ONLY CHANGE IN COMPOSITION AND STRUCTURE OVER TIME, BUT CAN BE DEGRADED VIA EXTRACELLULAR AND INTRACELLULAR PROTEASES. ALTHOUGH TRANSFORMING GROWTH FACTOR BETA APPEARS TO BE THE PRIMARY DRIVER OF KIDNEY FIBROSIS, A VAST ARRAY OF ADDITIONAL MOLECULES MAY HAVE MODULATING ROLES. THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IS INCREASINGLY APPRECIATED. AN INTRIGUING BUT INCOMPLETELY UNDERSTOOD CARDIORENAL SYNDROME UNDERLIES THE HIGH MORBIDITY AND MORTALITY RATES THAT DEVELOP IN ASSOCIATION WITH PROGRESSIVE KIDNEY FIBROSIS. 2014 7 3885 36 KIDNEY FIBROSIS: FROM MECHANISMS TO THERAPEUTIC MEDICINES. CHRONIC KIDNEY DISEASE (CKD) IS ESTIMATED TO AFFECT 10-14% OF GLOBAL POPULATION. KIDNEY FIBROSIS, CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION LEADING TO SCARRING, IS A HALLMARK MANIFESTATION IN DIFFERENT PROGRESSIVE CKD; HOWEVER, AT PRESENT NO ANTIFIBROTIC THERAPIES AGAINST CKD EXIST. KIDNEY FIBROSIS IS IDENTIFIED BY TUBULE ATROPHY, INTERSTITIAL CHRONIC INFLAMMATION AND FIBROGENESIS, GLOMERULOSCLEROSIS, AND VASCULAR RAREFACTION. FIBROTIC NICHE, WHERE ORGAN FIBROSIS INITIATES, IS A COMPLEX INTERPLAY BETWEEN INJURED PARENCHYMA (LIKE TUBULAR CELLS) AND MULTIPLE NON-PARENCHYMAL CELL LINEAGES (IMMUNE AND MESENCHYMAL CELLS) LOCATED SPATIALLY WITHIN SCARRING AREAS. ALTHOUGH THE MECHANISMS OF KIDNEY FIBROSIS ARE COMPLICATED DUE TO THE KINDS OF CELLS INVOLVED, WITH THE HELP OF SINGLE-CELL TECHNOLOGY, MANY KEY QUESTIONS HAVE BEEN EXPLORED, SUCH AS WHAT KIND OF RENAL TUBULES ARE PROFIBROTIC, WHERE MYOFIBROBLASTS ORIGINATE, WHICH IMMUNE CELLS ARE INVOLVED, AND HOW CELLS COMMUNICATE WITH EACH OTHER. IN ADDITION, GENETICS AND EPIGENETICS ARE DEEPER MECHANISMS THAT REGULATE KIDNEY FIBROSIS. AND THE REVERSIBLE NATURE OF EPIGENETIC CHANGES INCLUDING DNA METHYLATION, RNA INTERFERENCE, AND CHROMATIN REMODELING, GIVES AN OPPORTUNITY TO STOP OR REVERSE KIDNEY FIBROSIS BY THERAPEUTIC STRATEGIES. MORE MARKETED (E.G., RAS BLOCKAGE, SGLT2 INHIBITORS) HAVE BEEN DEVELOPED TO DELAY CKD PROGRESSION IN RECENT YEARS. FURTHERMORE, A BETTER UNDERSTANDING OF RENAL FIBROSIS IS ALSO FAVORED TO DISCOVER BIOMARKERS OF FIBROTIC INJURY. IN THE REVIEW, WE UPDATE RECENT ADVANCES IN THE MECHANISM OF RENAL FIBROSIS AND SUMMARIZE NOVEL BIOMARKERS AND ANTIFIBROTIC TREATMENT FOR CKD. 2023 8 4381 46 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 9 4415 28 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 10 446 28 APABETALONE DOWNREGULATES FIBROTIC, INFLAMMATORY AND CALCIFIC PROCESSES IN RENAL MESANGIAL CELLS AND PATIENTS WITH RENAL IMPAIRMENT. EPIGENETIC MECHANISMS ARE IMPLICATED IN TRANSCRIPTIONAL PROGRAMS DRIVING CHRONIC KIDNEY DISEASE (CKD). APABETALONE IS AN ORALLY AVAILABLE INHIBITOR OF BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS, WHICH ARE EPIGENETIC READERS THAT MODULATE GENE EXPRESSION. IN THE PHASE 3 BETONMACE TRIAL, APABETALONE REDUCED RISK OF MAJOR ADVERSE CARDIAC EVENTS (MACE) BY 50% IN THE CKD SUBPOPULATION, INDICATING FAVORABLE EFFECTS ALONG THE KIDNEY-HEART AXIS. ACTIVATION OF HUMAN RENAL MESANGIAL CELLS (HRMCS) TO A CONTRACTILE PHENOTYPE THAT OVERPRODUCES EXTRACELLULAR MATRIX (ECM) AND INFLAMMATORY CYTOKINES, AND PROMOTES CALCIFICATION, FREQUENTLY ACCOMPANIES CKD TO DRIVE PATHOLOGY. HERE, WE SHOW APABETALONE DOWNREGULATED HRMC ACTIVATION WITH TGF-BETA1 STIMULATION BY SUPPRESSING TGF-BETA1-INDUCED ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION, ALPHA-SMA ASSEMBLY INTO STRESS FIBERS, ENHANCED CONTRACTION, COLLAGEN OVERPRODUCTION, AND EXPRESSION OF KEY DRIVERS OF FIBROSIS, INFLAMMATION, OR CALCIFICATION INCLUDING THROMBOSPONDIN, FIBRONECTIN, PERIOSTIN, SPARC, INTERLEUKIN 6, AND ALKALINE PHOSPHATASE. LIPOPOLYSACCHARIDE-STIMULATED EXPRESSION OF INFLAMMATORY GENES IL6, IL1B, AND PTGS2 WAS ALSO SUPPRESSED. TRANSCRIPTOMICS CONFIRMED APABETALONE AFFECTED GENE SETS OF ECM REMODELING AND INTEGRINS. CLINICAL TRANSLATION OF IN VITRO RESULTS WAS INDICATED IN CKD PATIENTS WHERE A SINGLE DOSE OF APABETALONE REDUCED PLASMA LEVELS OF KEY PRO-FIBROTIC AND INFLAMMATORY MARKERS, AND INDICATED INHIBITION OF TGF-BETA1 SIGNALING. WHILE PLASMA PROTEINS CANNOT BE TRACED TO THE KIDNEY ALONE, ANTI-FIBROTIC AND ANTI-INFLAMMATORY EFFECTS OF APABETALONE IDENTIFIED IN THIS STUDY ARE CONSISTENT WITH THE OBSERVED DECREASE IN CARDIOVASCULAR RISK IN CKD PATIENTS. 2023 11 5370 27 RECENT ADVANCES IN UNDERSTANDING OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED AS ANY CONDITION THAT CAUSES REDUCED KIDNEY FUNCTION OVER A PERIOD OF TIME. FIBROSIS, TUBULAR ATROPHY AND INTERSTITIAL INFLAMMATION ARE THE HALLMARK OF PATHOLOGICAL FEATURES IN CKD. REGARDLESS OF INITIAL INSULT, CKD HAS SOME COMMON PATHWAYS LEADING CKD TO END-STAGE KIDNEY DISEASE, INCLUDING HYPOXIA IN THE TUBULOINTERSTITIUM AND PROTEINURIA. RECENT ADVANCES IN GENOME EDITING TECHNOLOGIES AND STEM CELL RESEARCH GIVE GREAT INSIGHTS TO UNDERSTAND THE PATHOGENESIS OF CKD, INCLUDING IDENTIFICATIONS OF THE ORIGINS OF RENAL MYOFIBROBLASTS AND TUBULAR EPITHELIAL CELLS UPON INJURY. ENVIRONMENTAL FACTORS SUCH AS HYPOXIA, OXIDATIVE STRESS, AND EPIGENETIC FACTORS IN RELATION TO CKD ARE ALSO DISCUSSED. 2015 12 4047 25 MAIN PATHOGENIC MECHANISMS AND RECENT ADVANCES IN COPD PERIPHERAL SKELETAL MUSCLE WASTING. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A WORLDWIDE PREVALENT RESPIRATORY DISEASE MAINLY CAUSED BY TOBACCO SMOKE EXPOSURE. COPD IS NOW CONSIDERED AS A SYSTEMIC DISEASE WITH SEVERAL COMORBIDITIES. AMONG THEM, SKELETAL MUSCLE DYSFUNCTION AFFECTS AROUND 20% OF COPD PATIENTS AND IS ASSOCIATED WITH HIGHER MORBIDITY AND MORTALITY. ALTHOUGH THE HISTOLOGICAL ALTERATIONS ARE WELL CHARACTERIZED, INCLUDING MYOFIBER ATROPHY, A DECREASED PROPORTION OF SLOW-TWITCH MYOFIBERS, AND A DECREASED CAPILLARIZATION AND OXIDATIVE PHOSPHORYLATION CAPACITY, THE MOLECULAR BASIS FOR MUSCLE ATROPHY IS COMPLEX AND REMAINS PARTLY UNKNOWN. MAJOR DIFFICULTIES LIE IN PATIENT HETEROGENEITY, ACCESSING PATIENTS' SAMPLES, AND COMPLEX MULTIFACTORIAL PROCESS INCLUDING EXTRINSIC MECHANISMS, SUCH AS TOBACCO SMOKE OR DISUSE, AND INTRINSIC MECHANISMS, SUCH AS OXIDATIVE STRESS, HYPOXIA, OR SYSTEMIC INFLAMMATION. MUSCLE WASTING IS ALSO A HIGHLY DYNAMIC PROCESS WHOSE INVESTIGATION IS HAMPERED BY THE DIFFERENTIAL PROTEIN REGULATION ACCORDING TO THE STAGE OF ATROPHY. IN THIS REVIEW, WE REPORT AND DISCUSS RECENT DATA REGARDING THE MOLECULAR ALTERATIONS IN COPD LEADING TO IMPAIRED MUSCLE MASS, INCLUDING INFLAMMATION, HYPOXIA AND HYPERCAPNIA, MITOCHONDRIAL DYSFUNCTION, DIVERSE METABOLIC CHANGES SUCH AS OXIDATIVE AND NITROSATIVE STRESS AND GENETIC AND EPIGENETIC MODIFICATIONS, ALL LEADING TO AN IMPAIRED ANABOLIC/CATABOLIC BALANCE IN THE MYOCYTE. WE RECAPITULATE DATA CONCERNING SKELETAL MUSCLE DYSFUNCTION OBTAINED IN THE DIFFERENT RODENT MODELS OF COPD. FINALLY, WE PROPOSE SEVERAL PATHWAYS THAT SHOULD BE INVESTIGATED IN COPD SKELETAL MUSCLE DYSFUNCTION IN THE FUTURE. 2023 13 307 34 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 14 1665 35 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 15 4543 28 MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON CAUSES AND BIOLOGICAL FINDINGS. RESPIRATORY AND/OR LIMB MUSCLE DYSFUNCTION, WHICH ARE FREQUENTLY OBSERVED IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS, CONTRIBUTE TO THEIR DISEASE PROGNOSIS IRRESPECTIVE OF THE LUNG FUNCTION. MUSCLE DYSFUNCTION IS CAUSED BY THE INTERACTION OF LOCAL AND SYSTEMIC FACTORS. THE KEY DELETERIOUS ETIOLOGIC FACTORS ARE PULMONARY HYPERINFLATION FOR THE RESPIRATORY MUSCLES AND DECONDITIONING SECONDARY TO REDUCED PHYSICAL ACTIVITY FOR LIMB MUSCLES. NONETHELESS, CIGARETTE SMOKE, SYSTEMIC INFLAMMATION, NUTRITIONAL ABNORMALITIES, EXERCISE, EXACERBATIONS, ANABOLIC INSUFFICIENCY, DRUGS AND COMORBIDITIES ALSO SEEM TO PLAY A RELEVANT ROLE. ALL THESE FACTORS MODIFY THE PHENOTYPE OF THE MUSCLES, THROUGH THE INDUCTION OF SEVERAL BIOLOGICAL PHENOMENA IN PATIENTS WITH COPD. WHILE RESPIRATORY MUSCLES IMPROVE THEIR AEROBIC PHENOTYPE (PERCENTAGE OF OXIDATIVE FIBERS, CAPILLARIZATION, MITOCHONDRIAL DENSITY, ENZYME ACTIVITY IN THE AEROBIC PATHWAYS, ETC.), LIMB MUSCLES EXHIBIT THE OPPOSITE PHENOTYPE. IN ADDITION, BOTH MUSCLE GROUPS SHOW OXIDATIVE STRESS, SIGNS OF DAMAGE AND EPIGENETIC CHANGES. HOWEVER, FIBER ATROPHY, INCREASED NUMBER OF INFLAMMATORY CELLS, ALTERED REGENERATIVE CAPACITY; SIGNS OF APOPTOSIS AND AUTOPHAGY, AND AN IMBALANCE BETWEEN PROTEIN SYNTHESIS AND BREAKDOWN ARE RATHER CHARACTERISTIC FEATURES OF THE LIMB MUSCLES, MOSTLY IN PATIENTS WITH REDUCED BODY WEIGHT. DESPITE THAT SIGNIFICANT PROGRESS HAS BEEN ACHIEVED IN THE LAST DECADES, FULL ELUCIDATION OF THE SPECIFIC ROLES OF THE TARGET BIOLOGICAL MECHANISMS INVOLVED IN COPD MUSCLE DYSFUNCTION IS STILL REQUIRED. SUCH AN ACHIEVEMENT WILL BE CRUCIAL TO ADEQUATELY TACKLE WITH THIS RELEVANT CLINICAL PROBLEM OF COPD PATIENTS IN THE NEAR-FUTURE. 2015 16 444 25 AORTIC AND CAROTID ARTERIAL STIFFNESS AND EPIGENETIC REGULATOR GENE EXPRESSION CHANGES PRECEDE BLOOD PRESSURE RISE IN STROKE-PRONE DAHL SALT-SENSITIVE HYPERTENSIVE RATS. MULTIPLE CLINICAL STUDIES SHOW THAT ARTERIAL STIFFNESS, MEASURED AS PULSE WAVE VELOCITY (PWV), PRECEDES HYPERTENSION AND IS AN INDEPENDENT PREDICTOR OF HYPERTENSION END ORGAN DISEASES INCLUDING STROKE, CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE. RISK FACTOR STUDIES FOR ARTERIAL STIFFNESS IMPLICATE AGE, HYPERTENSION AND SODIUM. HOWEVER, CAUSAL MECHANISMS LINKING RISK FACTOR TO ARTERIAL STIFFNESS REMAIN TO BE ELUCIDATED. HERE, WE STUDIED THE CAUSAL RELATIONSHIP OF ARTERIAL STIFFNESS AND HYPERTENSION IN THE NA-INDUCED, STROKE-PRONE DAHL SALT-SENSITIVE (S) HYPERTENSIVE RAT MODEL, AND ANALYZED PUTATIVE MOLECULAR MECHANISMS. STROKE-PRONE AND NON-STROKE-PRONE MALE AND FEMALE RATS WERE STUDIED AT 3- AND 6-WEEKS OF AGE FOR ARTERIAL STIFFNESS (PWV, STRAIN), BLOOD PRESSURE, VESSEL WALL HISTOLOGY, AND GENE EXPRESSION CHANGES. STUDIES SHOWED THAT INCREASED LEFT CAROTID AND AORTIC ARTERIAL STIFFNESS PRECEDED HYPERTENSION, PULSE PRESSURE WIDENING, AND STRUCTURAL WALL CHANGES AT THE 6-WEEK TIME-POINT. INSTEAD, DIFFERENTIAL GENE INDUCTION WAS DETECTED IMPLICATING MOLECULAR-FUNCTIONAL CHANGES IN EXTRACELLULAR MATRIX (ECM) STRUCTURAL CONSTITUENTS, MODIFIERS, CELL ADHESION, AND MATRICELLULAR PROTEINS, AS WELL AS IN ENDOTHELIAL FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATORS. IMMUNOSTAINING TESTING HISTONE MODIFIERS EP300, HDAC3, AND PRMT5 LEVELS CONFIRMED CAROTID ARTERY-UPREGULATION IN ALL THREE LAYERS: ENDOTHELIAL, SMOOTH MUSCLE AND ADVENTITIAL CELLS. OUR STUDY RECAPITULATES OBSERVATIONS IN HUMANS THAT GIVEN SALT-SENSITIVITY, INCREASED NA-INTAKE INDUCED ARTERIAL STIFFNESS BEFORE HYPERTENSION, INCREASED PULSE PRESSURE, AND STRUCTURAL VESSEL WALL CHANGES. DIFFERENTIAL GENE EXPRESSION CHANGES ASSOCIATED WITH ARTERIAL STIFFNESS SUGGEST A MOLECULAR MECHANISM LINKING SODIUM TO FULL-VESSEL WALL RESPONSE AFFECTING GENE-NETWORKS INVOLVED IN VASCULAR ECM STRUCTURE-FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATION. 2014 17 221 44 ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. BACKGROUND: ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY RENAL RECOVERY, IS A RISK FACTOR FOR THE FUTURE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD). IN THE PREVIOUS YEARS, NOVEL INSIGHTS IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION SUGGESTED A CAUSAL LINK BETWEEN AKI AND CKD DUE TO A MALADAPTIVE REPAIR AFTER SEVERE AND REPEATED INJURY. SUMMARY: SEVERAL PATHOLOGICAL MECHANISMS HAVE BEEN PROPOSED TO CONTRIBUTE TO THE PROGRESSION OF AKI AND TRANSITION TO CKD/ESRD INCLUDING HYPOXIA AND MICROVASCULAR RAREFACTION, ALTERATIONS OF RENAL RESIDENT CELL PHENOTYPES AND FUNCTIONS, CELL CYCLE ARREST IN THE G2/M PHASE, PERSISTENT CHRONIC INFLAMMATION, AND DEVELOPMENT OF INTERSTITIAL FIBROSIS, MITOCHONDRIAL FRAGMENTATION, EPIGENETIC CHANGES, ACTIVATION OF RENIN-ANGIOTENSIN SYSTEM (RAS), CELL AND TISSUE SENESCENCE. FURTHERMORE, SEVERAL CLINICAL FACTORS HAVE BEEN IDENTIFIED SUCH AS SEVERITY OF AKI, AGE, AND COMORBIDITIES. THE IDENTIFICATION OF AKI-TO-CKD BIOMARKERS COULD IMPROVE THE EARLY IDENTIFICATION OF AKI PATIENTS WITH HIGHER RISK FOR CKD PROGRESSION. HOWEVER, ALTHOUGH OUR UNDERSTANDING IN THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION IS SIGNIFICANTLY IMPROVED, NO NOVEL INTERVENTION HAS BEEN VALIDATED. POTENTIAL THERAPEUTIC APPROACHES TO TREAT AKI AND BLOCK THE TRANSITION TO CKD/ESRD HAVE BEEN RECENTLY REPORTED, BUT THEY NEED FURTHER VALIDATIONS. KEY MESSAGES: MALADAPTIVE REPAIR AFTER AKI IS STRONGLY ASSOCIATED TO THE DEVELOPMENT OF CKD AND LONG-TERM CONSEQUENCES. THE PROMPT IDENTIFICATION OF PATIENTS AT HIGHER RISK FOR LATE CKD PROGRESSION AND THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS REMAIN CRITICAL RESEARCH GOALS. 2018 18 6446 32 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 19 933 31 CHRONIC KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD) HAVE EVOLVED OVER TIME, BUT CURRENT INTERNATIONAL GUIDELINES DEFINE THIS CONDITION AS DECREASED KIDNEY FUNCTION SHOWN BY GLOMERULAR FILTRATION RATE (GFR) OF LESS THAN 60 ML/MIN PER 1.73 M(2), OR MARKERS OF KIDNEY DAMAGE, OR BOTH, OF AT LEAST 3 MONTHS DURATION, REGARDLESS OF THE UNDERLYING CAUSE. DIABETES AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ALL HIGH-INCOME AND MIDDLE-INCOME COUNTRIES, AND ALSO IN MANY LOW-INCOME COUNTRIES. INCIDENCE, PREVALENCE, AND PROGRESSION OF CKD ALSO VARY WITHIN COUNTRIES BY ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH, POSSIBLY THROUGH EPIGENETIC INFLUENCE. MANY PEOPLE ARE ASYMPTOMATIC OR HAVE NON-SPECIFIC SYMPTOMS SUCH AS LETHARGY, ITCH, OR LOSS OF APPETITE. DIAGNOSIS IS COMMONLY MADE AFTER CHANCE FINDINGS FROM SCREENING TESTS (URINARY DIPSTICK OR BLOOD TESTS), OR WHEN SYMPTOMS BECOME SEVERE. THE BEST AVAILABLE INDICATOR OF OVERALL KIDNEY FUNCTION IS GFR, WHICH IS MEASURED EITHER VIA EXOGENOUS MARKERS (EG, DTPA, IOHEXOL), OR ESTIMATED USING EQUATIONS. PRESENCE OF PROTEINURIA IS ASSOCIATED WITH INCREASED RISK OF PROGRESSION OF CKD AND DEATH. KIDNEY BIOPSY SAMPLES CAN SHOW DEFINITIVE EVIDENCE OF CKD, THROUGH COMMON CHANGES SUCH AS GLOMERULAR SCLEROSIS, TUBULAR ATROPHY, AND INTERSTITIAL FIBROSIS. COMPLICATIONS INCLUDE ANAEMIA DUE TO REDUCED PRODUCTION OF ERYTHROPOIETIN BY THE KIDNEY; REDUCED RED BLOOD CELL SURVIVAL AND IRON DEFICIENCY; AND MINERAL BONE DISEASE CAUSED BY DISTURBED VITAMIN D, CALCIUM, AND PHOSPHATE METABOLISM. PEOPLE WITH CKD ARE FIVE TO TEN TIMES MORE LIKELY TO DIE PREMATURELY THAN THEY ARE TO PROGRESS TO END STAGE KIDNEY DISEASE. THIS INCREASED RISK OF DEATH RISES EXPONENTIALLY AS KIDNEY FUNCTION WORSENS AND IS LARGELY ATTRIBUTABLE TO DEATH FROM CARDIOVASCULAR DISEASE, ALTHOUGH CANCER INCIDENCE AND MORTALITY ARE ALSO INCREASED. HEALTH-RELATED QUALITY OF LIFE IS SUBSTANTIALLY LOWER FOR PEOPLE WITH CKD THAN FOR THE GENERAL POPULATION, AND FALLS AS GFR DECLINES. INTERVENTIONS TARGETING SPECIFIC SYMPTOMS, OR AIMED AT SUPPORTING EDUCATIONAL OR LIFESTYLE CONSIDERATIONS, MAKE A POSITIVE DIFFERENCE TO PEOPLE LIVING WITH CKD. INEQUITY IN ACCESS TO SERVICES FOR THIS DISEASE DISPROPORTIONALLY AFFECTS DISADVANTAGED POPULATIONS, AND HEALTH SERVICE PROVISION TO INCENTIVISE EARLY INTERVENTION OVER PROVISION OF CARE ONLY FOR ADVANCED CKD IS STILL EVOLVING IN MANY COUNTRIES. 2017 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