Document text
Principal Investigator: Michael P Hutchens
Organization: PORTLAND VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Acute cardiorenal syndrome (cardiorenal syndrome type 1, CRS1) frequently follows the most common cause
of admission to a Veterans Health Administration inpatient facility, acute cardiovascular disease. Although
CRS1 seems to self-resolve in most cases, development of chronic kidney disease often occurs rapidly
afterward (within 1-2 years). Animal studies demonstrate there is mechanistic connection between CRS1 and
early onset CKD, a form of AKI-CKD transition. The long term goal is to determine mechanisms of long-term
outcomes of CRS1 with a focus on the potential for translational intervention. The proposed work is focused
on whether and how CRS1 induces further cardiovascular disease commonly comorbid with CKD. Published
data generated in a mouse model of CRS1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR)
demonstrate that despite recovery of renal function 2 weeks after CA/CPR, CKD ubiquitously occurs by 7
weeks after CA/CPR. Data generated for this proposal show that 7 weeks after CA/CPR, mice have
developed systemic hypertension with associated changes in renal vascular architecture and myocardial wall
thickness. Tantalizingly, CKD and systemic hypertension are recapitulated by injection of a soluble cardiac-
derived factor, CSRP3, which is released into the plasma after CA/CPR. CSRP3 functions as transcriptional
activator of the myogenesis pathway in cardiac development. Data suggest that CSRP3 mediates the renin-
angiotensin system through angiotensin-converting enzyme 2 (ACE2) in the renal proximal tubule. Therefore
the central hypothesis in this proposal is acute cardiorenal syndrome causes chronic systemic hypertension via
CSRP3-induced, myogenesis-mediated reduction of proximal tubule ACE2 activity. The specific hypothesis is
that that the myogenesis factor MyoD is induced in proximal tubule epithelial cells by CSRP3 exposure, and in
turn represses ACE2 membrane distribution. This hypothesis will be investigated in two specific aims. Aim 1
will determine the mechanism by which CRS1 causes chronic systemic hypertension in vivo. Wild-type mice,
and mice with inducible, cardiac-specific deletion of CSRP3, or deletion of proximal tubule ACE2 will be
subjected to CA/CPR. It is hypothesized that in the absence of cardiac CSRP3, hypertension will be blunted,
while in the absence of ACE2 in the proximal tubule, hypertension will be exacerbated. Blood pressure will be
assessed in awake, unrestrained mice 7 weeks after CA/CPR using radiotelemetry, and renal function,
myogenesis determination genes, and components of the renin-angiotensin system including ACE2 will be
assessed using qPCR, immunoblotting, and renal immunofluorescence. Heart and kidney sections will be
assessed to determine whether myocardial wall thickness and renal arcuate arterial wall thickness are altered.
Translational experiments will determine plasma CSRP3 levels in deidentified patients with cardiac disease,
and test whether pharmacologic inhibition of CSRP3 uptake in the kidney ameliorates development of
hypertension in mice. Aim 2 will delineate the mechanism of proximal tubule epithelial cell functional change in
vitro, and will be performed in primary culture of human proximal tubule epithelial cells. To test the hypothesis
that CSRP3 induces proximal tubule epithelial cell functional change including reduction of ACE2 polarity via
regulation of myogenesis determination genes, cells will be exposed to recombinant CSRP3, vehicle, and
relevant protein controls. To model the inflammatory environment in the AKI-CKD kidney, transforming growth
factor beta will be used to costimulate cells in addition to CSRP3 alone. qPCR, immunofluorescence, and
immunoblotting will be used to assess ACE2, myogenesis determination gene transcripts, expression, and
distribution. Effects on ACE2 polarity and function will be evaluated. shRNA interference will be used to knock
down expression of critical pathway mediators including myogenic differentiation antigen (MyoD). The studies
proposed here test mechanisms of interaction between the injured heart and kidney, and will delineate an
important pathway by which CRS1 leads to chronic cardiorenal disease.
Terms: <ACE2><Acute><Admission><Admission activity><Animals><Architecture><Asystole><BP homeostasis><BP regulation><Blood Plasma><Blood Pressure><Bone-Derived Transforming Growth Factor><Cardiac><Cardiac Arrest><Cardiac Diseases><Cardiac Disorders><Cardiac development><Cardiopulmonary Resuscitation><Cardiorenal disease><Cardiorenal dysfunction><Cardiorenal syndrome><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cell surface><Cell-Extracellular Matrix><Cells><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Critical Paths><Critical Pathways><Data><Development><Differentation Markers><Differentiation Antigens><Differentiation Markers><Disease><Disorder><Drug Therapy><ECM><Endocrine><Endocytosis><Engineering / Architecture><Epithelial Cells><Epithelium><Exposure to><Extracellular Matrix><GP330 Antigen><Gene Deletion><Gene Transcription><Genes><Genetic Transcription><Glycoprotein 330><Goals><Health><Heart><Heart Arrest><Heart Diseases><Heart Injuries><Heyman's Nephritis Antigen GP330><Heymann Nephritis Antigen GP330><Histology><Hospital Admission><Hospitalization><Human><Hypertension><Hypertrophy><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><In Vitro><Injections><Inpatients><Interruption><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Kidney><Kidney Diseases><Kidney Urinary System><LDL-Receptor Related Protein 2><LRP-2><LRP-2 Receptor><Laboratories><Left Ventricular Hypertrophy><Low-Density Lipoprotein Receptor-Related Protein-2><Marker Antigens><Mediating><Mediator><Medical center><Megalin><Membrane><Methods><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Murine><Mus><Muscle><Muscle Cells><Muscle Tissue><Myocardial><Myocytes><Nephritis Antigen GP 330><Nephropathy><Nephrosclerosis><Outcome><Pathway interactions><Patients><Pharmacotherapy><Phenotype><Plasma><Plasma Serum><Platelet Transforming Growth Factor><Proteins><Proximal Kidney Tubules><Public Health><Publishing><RNA Expression><Recombinants><Recovery><Regulation><Renal Disease><Renal Glycoprotein GP330><Renal Vascular><Renal function><Renal vessels><Renin-Angiotensin System><Repression><Research><Reticuloendothelial System, Serum, Plasma><Role><Signal Transduction><Signal Transduction Systems><Signaling><Systemic hypertension><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic Intervention><Thick><Thickness><Transcript><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Regulation><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transcriptional Control><Transcriptional Regulation><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Translational Research><Translational Science><Tubular><Tubular formation><United States Department of Veterans Affairs><United States Veterans Administration><Urine><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Ventricle Remodeling><Ventricular Cardiac Remodeling><Ventricular Myocardial Remodeling><Ventricular Remodeling><Veterans><Veterans Administration><Veterans Affairs><Veterans Health Administration><Veterans Health Affairs><Western Blotting><Western Immunoblotting><Wild Type Mouse><Work><angiotensin converting enzyme 2><angiotensin converting enzyme II><apical membrane><awake><biological signal transduction><blood pressure homeostasis><blood pressure regulation><cardiac injury><cardiac resuscitation><cardiogenesis><cardiovascular disorder><cellular differentiation><chronic kidney disease><co-morbid><co-morbidity><comorbidity><developmental><drug treatment><early onset><experiment><experimental research><experimental study><experiments><gene deletion mutation><gp 330><heart development><heart disorder><heart formation><heart resuscitation><high blood pressure><hyperpiesia><hyperpiesis><hypertensive><hypertensive disease><hypertensive disorder><improved><in vivo><inflammatory environment><inflammatory milieu><intervention therapy><interventional strategy><kidney disorder><kidney fibrosis><kidney function><kidney vascular><kidney vascular structure><knock-down><knockdown><long-term sequelae><membrane structure><mouse model><murine model><muscular><myocardial remodeling><myogenesis><novel><pathway><pharmacologic><prevent><preventing><protein blotting><regulate BP><regulate blood pressure><release factor><renal><renal disorder><renal epithelium><renal fibrosis><renal proximal tubule><renal sclerosis><renovascular><response><shRNA><short hairpin RNA><small hairpin RNA><social role><transcription co-activator><transcriptional co-activator><translation research><translational investigation><translational model><translational opportunities><translational potential><uptake><wildtype mouse>