Mechanistic Underpinnings of Chronic Kidney Disease Initiated by Acute Cardiorenal Syndrome
急性心肾综合征引发的慢性肾脏病的机制基础
基本信息
- 批准号:10436781
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute DiseaseAcute Renal Failure with Renal Papillary NecrosisAlbuminsAnesthesia proceduresAnimal ModelAnimalsBasic ScienceCardiacCardiac developmentCardiopulmonary ResuscitationCardiovascular DiseasesCardiovascular systemCarrier ProteinsCell NucleusCellsChestChronicChronic Kidney FailureChronic Kidney InsufficiencyCicatrixClinicalClinical ResearchDataDevelopmentDialysis procedureEndocytosisEpinephrineEpithelialEpithelial CellsExposure toExtracellular Matrix ProteinsFDA approvedFibrosisFiltrationFluorescenceGenesGenetic TranscriptionGlomerular Filtration RateHK2 geneHeartHeart ArrestHeart DiseasesHeart InjuriesHeart failureHospitalizationHourHumanImmunohistochemistryImpairmentIn VitroInflammatory ResponseInjectionsInjuryInjury to KidneyInterruptionInterventionInvestigationIschemiaIsofluraneKidneyKidney DiseasesLDL-Receptor Related Protein 2Length of StayLinkMediatingMethodsMicropunctureModelingMosaicismMouse StrainsMusMyocardial InfarctionNuclearOrganPatientsPharmaceutical PreparationsPlasmaPotassium ChloridePrevalencePrevention strategyProteinsRecombinant ProteinsRecombinantsRenal functionReperfusion TherapyReporterResuscitationRiskRoleSignal TransductionSurvivorsSyndromeSystemTestingTissuesTransplantationTubular formationUrineVeteransWestern BlottingWorkartery occlusionbasecardiovascular disorder riskcoronary fibrosisfibrous proteinglomerular filtrationhigh riskin vivoinnovationkidney cellkidney dysfunctionkidney fibrosislentiviral-mediatedmilitary veteranmouse modelnanoproteomicnovelpreventreceptorrenal arterytherapy designtranslational modeltranslational studytreatment strategyuptake
项目摘要
Acute cardiorenal syndrome imperils the survival of half of cardiac arrest survivors and that of many patients
with myocardial infarction or acute heart failure. Patients who survive have high risk of chronic kidney disease
(CKD). The hypothesis in this proposal is that cardiac arrest and cardiopulmonary resuscitation in the mouse
(CA/CPR) causes filtration and tubular endocytosis of cardiac LIM protein (CSRP3), a soluble inducer of renal
fibrosis, which initiates chronic kidney disease via Wingless (Wnt)-effector activation in renal tubular
epithelium. The objectives in this proposal are:
1) Establish whether a soluble factor explains the potent induction of CKD by CA/CPR , 2) Determine whether
tubular endocytosis of CSRP3 via the endocytic receptor megalin leads to renal fibrosis, and 3) Determine the
intracellular mechanism of fibrosis induction by CSRP3.
Aim 1 tests the hypothesis that CA/CPR potently induces CKD via a soluble factor from the heart. CA/CPR will
be performed in mice with deletion of cardiac CSRP3, and CSRP3 will be administered to mice with deletion of
cardiac CSRP3 to recapitulate the wild-type injury. Renal fibrosis glomerular filtration rate and urine protein will
be quantified. Aim 2 tests the hypothesis that functional endocytosis via the tubular epithelial receptor megalin
is required for development of CA/CPR-induced renal fibrosis. CA/CPR will be performed in mice with
conditional, proximal tubular-specific deletion of megalin (and littermate controls). 7 weeks later mice will be
tested for chronic kidney disease, quantifying fibrosis, glomerular filtration rate, and urine protein. Aim 3 tests
the hypothesis that CSRP3 translocates to the tubular epithelial cell nucleus and induces Wnt effector genes.
Tubular epithelial cells will be exposed to CSRP3, and a Wnt-effector reporter system and immunoblotting and
immunohistochemistry used to determine Wnt effector transcription, and localize CSRP3.
Methods: Murine CA/CPR will be employed in aim 1 and aim 2. Briefly, under isoflurane anesthesia, cardiac
arrest is induced with potassium chloride and resuscitated 8 min later with chest compressions and
epinephrine, analogous to resuscitation of cardiac arrest in humans. Preliminary data indicate that 7 weeks
after CA/CPR, there is robust induction of renal fibrosis and reduction in glomerular filtration rate. Aim 1
employs mice with inducible deletion of cardiac CSRP3. Aim 2 will use 2 strains of mice with deletion of
proximal tubular megalin, one with mosaic and lifelong deletion, and the second with inducible, complete
deletion of megalin. CA/CPR and recombinant CSRP3 administration will be employed in these two strains to
test the involvement of megalin. Aim 3 will be conducted in vitro, using immortalized human tubular epithelial
cells (the HK2 line). Cells will be transfected with a Wnt reporter system (TOPFlash) which yields fluorescence
proportional to transcription of Wnt effector genes. TOPFlash will be used to test the effect of recombinant
CSRP3 administration in cells with lentiviral-mediated megalin interference. To test whether CSRP3 undergoes
nuclear localization, immunohistochemistry will be used.
This study is derived from clinical observation that acute cardiorenal syndrome increases risk of chronic
kidney disease. The model employed, murine CA/CPR, is uniquely translational among models of acute
disease causing chronic renal insufficiency. Our study evaluates a novel mechanism by which cardiac disease
causes renal disease. We test intervention in this mechanism for which an FDA-approved medication which
could be applied in humans is available, should clinical study corroborate our basic science findings. Veterans
suffer from greatly elevated risk of cardiovascular disease, chronic kidney injury, and cardiorenal syndrome.
This study tests a novel mechanism connecting cardiovascular disease and chronic kidney disease; therapy
derived from this study could therefore reduce the burden of chronic kidney disease on US military veterans.
急性心肾综合征危及一半的心脏骤停幸存者和许多患者的生存
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael P Hutchens其他文献
Michael P Hutchens的其他文献
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{{ truncateString('Michael P Hutchens', 18)}}的其他基金
Mechanistic Underpinnings of Chronic Kidney Disease Initiated by Acute Cardiorenal Syndrome
急性心肾综合征引发的慢性肾脏病的机制基础
- 批准号:
10554295 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Mechanistic Underpinnings of Chronic Kidney Disease Initiated by Acute Cardiorenal Syndrome
急性心肾综合征引发的慢性肾脏病的机制基础
- 批准号:
9892583 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action
心脏骤停后肾损伤的性别差异:雌激素作用机制
- 批准号:
8464084 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action
心脏骤停后肾损伤的性别差异:雌激素作用机制
- 批准号:
8300044 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action
心脏骤停后肾损伤的性别差异:雌激素作用机制
- 批准号:
8189792 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action
心脏骤停后肾损伤的性别差异:雌激素作用机制
- 批准号:
8661172 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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