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Principal Investigator: Takuto Greco Chiba
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $119,857
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ ABSTRACT
A dire consequence of acute kidney injury (AKI) is a dramatically increased risk to develop chronic kidney disease
(CKD). CKD accounts for 6.7% of Medicare expenses. Understanding the mechanisms by which AKI progresses
to CKD is essential for developing therapies, for which none currently exist. Renal microvasculature, including
pericytes and endothelial cells, are damaged in AKI, leading to recruitment of inflammatory cells which
contributes to progression to CKD. However, cellular, and molecular mechanisms that drive this process are
largely unknown. Pericytes are a heterogeneous mesenchymal population and have been identified as a major
source of myofibroblasts that drives CKD. Understanding the molecular mechanisms that mediates maladaptive
endothelial-pericyte crosstalk leading to exacerbated and prolonged inflammation could drive therapeutic
exploitation of this phenomenon. Previously, it has been shown that the systemic blockade of Vascular
endothelial growth factor receptor 2 (VEGF-R2) blocks CKD progression. My preliminary data, knocking out
VegfR2 in renal stromally derived cells (RSC) (termed VegfR2RSC-/-) that includes pericytes, confirms the
protective nature of this loss-of-function. I found that, in CKD models by renal ischemia/ reperfusion injury (IRI)
as well as by cisplatin, VegfR2RSC-/- mice have attenuated CKD progression, along with having mitigated
inflammation and preserved vascular function. My bulk RNA-sequencing analysis with isolated RSCs
demonstrates that inflammatory pathways are activated while short-chain fatty acid metabolism pathways are
suppressed during AKI-to-CKD transition. Mechanistically, VegfR2RSC-/- kidneys (1) have reduced expression of
a pro-inflammatory signaling axis of Thrombospondin-1 (TSP1)/ CD148, and (2) have increased expression of
fatty acid metabolism associated genes contributing to the enhanced protection. To home in on the timing of the
protection, I have generated a tamoxifen-inducible RSC-specific VegfR2 knockout (iVegfR2RSC-/-) mouse. I found
that, after pre-treatment of tamoxifen, iVegfR2RSC-/- mice are significantly protected against AKI. Together, these
data informed my overarching hypothesis that renal pericyte-specific VEGF-R2 signaling dysregulates pericyte-
endothelial crosstalk stimulating inflammation to exacerbate CKD. I propose the following aims to test this: Aim
1 will test the hypothesis that pericyte-specific VEGF-R2 signaling exacerbates AKI-to-CKD transition. Aim 2 will
test the hypothesis that pericyte VEGF-R2 signaling mediates maladaptive pericyte-endothelial crosstalk to
exacerbate inflammation, promoting AKI-to-CKD. Aim 3 will test the hypothesis that inhibiting VegfR2 signaling
in renal pericytes enhances vascular repair, mitigates inflammation, and blocks progression to CKD after AKI.
For the K01 Award, I enlisted innovative mentors. The University of Pittsburgh has an extraordinary number of
faculty with research programs focused on AKI, and on vascular medicine. Successful completion of these
studies will shed light on how renal pericyte specific VEGF-R2 signaling exacerbates CKD progression.
Terms: <AAV vector><AAV-based vector><Acute Renal Failure with Renal Papillary Necrosis><Adeno-Associated Viruses><Adventitial Cell><Age><Asystole><Attenuated><Blood Vessels><CD148><CDDP><Cardiac Arrest><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cellular injury><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Co-culture><Cocultivation><Coculture><Coculture Techniques><Critical Illness><Critically Ill><Cysplatyna><DEP1><Data><Dependoparvovirus><Dependovirus><Dichlorodiammineplatinum><Disease><Disease Progression><Disorder><Endothelial Cells><Endothelium><Expenditure><FLK1><Faculty><Fatty Acid Metabolism Pathway><Fatty Acids><Female><Gene Modified><Genes><Health Insurance for Aged and Disabled, Title 18><Health Insurance for Disabled Title 18><Heart Arrest><Heterogeneity><Home><Human><In Situ Hybridization><In Vitro><Inflammation><Inflammatory><Injury><Injury to Kidney><Intracellular Communication and Signaling><Ischemia-Reperfusion Injury><K01 Award><K01 Mechanism><K01 Program><KDR gene><KO mice><Kidney><Kidney Diseases><Kidney Urinary System><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Mediating><Medicare><Medicine><Mentored Research Scientist Development Award><Mentored Training Award><Mentors><Mesenchymal><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Mouse Homolog of Susceptibility to Colon Cancer 1><Murine><Mus><Myofibroblast><Nature><Nephropathy><Null Mouse><PDGF><PDH kinase><PTPRJ><PTPRJ gene><Pathway interactions><Patients><Pericapillary Cell><Pericytes><Perivascular Cell><Peyrone's Chloride><Peyrone's Salt><Phenotype><Platelet-Derived Growth Factor><Platinum Diamminodichloride><Play><Population><Predictive Factor><Process><Production><Protein Tyrosine Phosphatase Receptor Type J><Protein-Tyrosine Phosphatase, ETA><RNA Seq><RNA sequencing><RNAseq><Renal Cell><Renal Disease><Reperfusion Damage><Reperfusion Injury><Reporter><Research><Research Scientist Development Award><Respiration><Risk><Role><Rouget Cells><SCC1><Short interfering RNA><Short-Chain Fatty Acids><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Source><TSP-1><TSP1><Tamoxifen><Testing><Therapeutic><Thrombospondin 1><Title 18><Universities><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Validation><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Volatile Fatty Acids><acute kidney injury><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><ages><attenuate><attenuates><biological signal transduction><cell damage><cell injury><cell sorting><cellular damage><chemotherapeutic agent><chronic kidney disease><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><damage to cells><develop therapy><disease model><disorder model><etomoxir><experiment><experimental research><experimental study><experiments><fatty acid metabolism><fatty acid oxidation><gene modification><genetically modified><health insurance for disabled><homes><in situ Hybridization Genetics><in situ Hybridization Staining Method><inhibitor><injuries><injury to cells><innovate><innovation><innovative><intervention development><kidney cell><kidney disorder><kidney injury><kidney ischemia><loss of function><male><mitochondrial><mouse model><murine model><pathway><pharmacologic><preservation><programs><pyruvate dehydrogenase kinase><recruit><renal><renal disorder><renal injury><renal ischemia><repair><repaired><respiratory mechanism><scRNA-seq><sex><siRNA><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutic evaluation><therapeutic testing><therapy development><transcriptome sequencing><transcriptomic sequencing><treatment development><validations><vascular>