Document text
Principal Investigator: DAVID SHEIKH-HAMAD
Organization: MICHAEL E DEBAKEY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
The prevalence of chronic kidney disease (CKD) in the US is rising concomitant with aging of the general
population and coexistence of comorbidities such as hypertension and diabetes mellitus. Cardiovascular
outcomes, sudden death and overall mortality are worse with advancing CKD. Ischemic kidney injury may
exacerbate other disease processes and accelerate the progression to ESKD. The underlying pathways and
contributing factors to the development and progression from AKI to CKD are poorly understood. Abnormalities in
mitochondrial function play critical roles in many disease processes. We have recently shown megalin is present
in the mitochondria, where it associates with stanniocalcin-1 (STC1) and SIRT3; two proteins that promote anti-
oxidant defenses. Internalization into the cell and shuttling of the intracrines angiotensin II, STC1 and TGF-β1 from
the cell surface to the mitochondria are megalin-dependent; deletion of megalin is associated with impaired
mitochondrial respiration and glycolysis. Megalin is found in clathrin-coated pits and provides endocytic receptor-
mediated ligand uptake. Here, we show tubular epithelium-specific KO of megalin aggravates AKI after
ischemia/reperfusion (I/R) and is associated with severe and sustained kidney inflammation, upregulation of TGF-
β1 and fibrosis, cell cycle arrest, mitochondrial stress, dysregulated lysosomal function and rapid progression to
CKD. Additionally, we show TGF-β1 is degraded by the mitochondrial caseinolytic protein proteases. We
hypothesize that megalin is a guardian of kidney health; megalin downregulates pathways of cellular
injury (inflammation, TGF-β1, fibrosis) and preserves recovery pathways (mitochondrial function,
lysosomal biogenesis); upregulation of megalin may be a therapeutic target to slow CKD progression.
Aim 1A will examine kidney injury, TGF-β1 signaling, fibrosis and progression to CKD in mice with tubular
epithelium-specific overexpression of megalin using post-I/R model. Aim 1B will examine the role of mitochondrial
caseinolytic protein proteases in the termination of TGF-β1 signaling. Aim 1C will examine the expression of cell
cycle regulators and TGF-β1 signaling after I/R in mice with combined conditional tubular epithelium specific
deletion of megalin and SMAD3. Aim 2 will examine the expression of signaling molecules involved in autophagy
and lysosomal biogenesis (mTOR, PGC1α, TFEB, ERK2 and calcineurin) and characterize lysosomal morphology
following hypoxia/reoxygenation in sgScramble and sgLrp2 BUMPT cells. This proposal will examine new
paradigms for megalin-mediated kidney protection and identify therapeutic targets to prevent CKD progression
after ischemic AKI.
Terms: <Acceleration><Acute><Acute Renal Failure with Renal Papillary Necrosis><Aging><AngII><Angiotensin II><Animal Experiments><Antioxidants><Attenuated><Autophagocytosis><Bioavailability><Biogenesis><Biological Availability><Biological Function><Biological Process><Bone-Derived Transforming Growth Factor><CCND1 Protein><Calcineurin><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Cycle Arrest><Cell Division Cycle><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell surface><Cells><Cellular Proliferation><Cellular injury><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clathrin><Cultured Cells><Cyclin D1><DNA Polymerase Delta Auxiliary Protein><Data><Degenerative Neurologic Disorders><Development><Diabetes Mellitus><Disease><Disease Progression><Disorder><Down-Regulation><ERK 2><ERK2><ERT1><Endocytosis><Endosomes><Epithelial Cells><Epithelium><Esteroproteases><Extracellular Signal-Regulated Kinase 2><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fibrosis><G1/S-Specific Cyclin D1><GP330 Antigen><General Population><General Public><Glycolysis><Glycoprotein 330><Goals><Health><Heart Vascular><Heyman's Nephritis Antigen GP330><Heymann Nephritis Antigen GP330><Human><Hypertension><Hypoxia><Hypoxic><Impairment><In Vitro><Inflammation><Injury to Kidney><Intracellular Communication and Signaling><Ischemia><JV15-2><Kidney><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Kinetics><LDL-Receptor Related Protein 2><LRP-2><LRP-2 Receptor><Ligands><Low-Density Lipoprotein Receptor-Related Protein-2><Lysosomes><MADH3><MADH3 gene><MAP Kinase 1><MAP Kinase 2><MAPK1><MAPK1 Mitogen-Activated Protein Kinase><MAPK1 gene><MAPK2><MAPK2 Mitogen-Activated Protein Kinase><Mechanistic Target of Rapamycin><Mediating><Megalin><Metabolic syndrome><Mice><Mice Mammals><Milk Growth Factor><Mitochondria><Mitogen Activated Protein Kinase 1><Mitogen-Activated Protein Kinase 2><Modeling><Modern Man><Morphology><Mothers Against Decapentaplegic, Drosophila, Homolog of, 3><Murine><Mus><Nephritis Antigen GP 330><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Origin of Life><Outcome><Oxygen Deficiency><P41MAPK><P42MAPK><PCNA-Cyclin><PP2B><PRAD1 Protein><PRKM1><PRKM2><Pathway interactions><Peptidases><Peptide Hydrolases><Physiologic Availability><Platelet Transforming Growth Factor><Play><Prevalence><Process><Proliferating Cell Nuclear Antigen><Protease Gene><Proteases><Protein Phosphatase-2B><Proteinases><Proteins><Proteolytic Enzymes><Proto-Oncogene Proteins c-bcl-1><Publishing><RAFT1><Receptor Protein><Receptosomes><Recovery><Renal Failure><Renal Glycoprotein GP330><Renal Insufficiency><Renal function><Reperfusion Therapy><Respiration><Role><SMA- and MAD-Related Protein 3><SMAD3><STC gene><STC protein><STC1><STC1 gene><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Stanniocalcin 1><Stress><Sudden Death><Surface><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Tubular><Tubular formation><Up-Regulation><Upregulation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><acute kidney injury><animal experiment><attenuate><attenuates><autophagy><bcl-1 Proto-Oncogene Products><bcl-1 Proto-Oncogene Proteins><bcl1 Proto-Oncogene Proteins><biological signal transduction><c-bcl-1 Proteins><cardiovascular disorder><cell damage><cell injury><cellular damage><chronic kidney disease><circulatory system><co-morbid><co-morbidity><coated pit><comorbidity><cyclin D><damage to cells><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diabetes><exosome><experimental animal><experimental animals><gp 330><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><in vivo><injury to cells><kidney fibrosis><kidney function><kidney injury><kidney ischemia><kidney preservation><mTOR><mammalian target of rapamycin><mitochondrial><mortality><neurodegenerative illness><overexpress><overexpression><p42 MAP Kinase><p42 MAPK><pathway><preservation><prevent><preventing><receptor><renal><renal fibrosis><renal injury><renal ischemia><reperfusion><respiratory mechanism><social role><stanniocalcin><therapeutic target><uptake>