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Non-canonical EphB2-mediated signaling in AKI and its progression to CKD

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Transforming growth factor (TGF)-β promotes inflammatory and fibrotic responses via activation of the serine/threonine kinase receptor TβRII and consequent activation of SMAD3. In the kidney, TGF-β is activated in acute kidney injury (AKI) and is associated with proximal tubule epithelial cell (PTEC) responses that lead to the development of and progression to chronic kidney disease (CKD). To this end, PTECs produce inflammatory cytokines, extracellular matrix, and stimulate differentiation of fibroblasts into myofibroblasts, the major producers of extracellular matrix and drivers of fibrosis. Although a role for TGF-β in AKI and CKD has been established, anti-TGF-β therapy has not yet translated into successful treatment in CKD patients. A possible explanation is that TβRII can be activated in a ligand-independent manner which potentiates low dose TGF-β signaling. We showed that the cytoplasmic tail of TβRII contains several tyrosines which can be phosphorylated in a TGF-β independent manner, leading to SMAD3 activation and fibrotic responses in kidney cells. We found that the tyrosine kinase EPH receptor B2 (EphB2) forms a complex with and phosphorylates TβRII. EphB2 is expressed by PTECs and it contributes to organ injury by promoting inflammation and fibrosis. However, the contribution of EphB2 to AKI-to-CKD progression and the cells responsible for its deleterious effects have not been investigated. Using a model of AKI that progresses to CKD, we show that pYEphB2 and pYTβRII are evident in the acute and chronic phases of kidney injury. Ephrin B1-mediated activation of EphB2 leads to pYTβRII and enhances TGF- β-induced SMAD3 activation and epithelial-to-mesenchymal transition. Mice treated with a novel EphB2 inhibitor showed reduced tubular injury, inflammation, collagen production as well as pYEphB2 and pYTβRII following ischemia/reperfusion-induced AKI. Interestingly, we found that macrophage inhibitor factor (MIF), a cytokine that contributes to inflammation following kidney injury, is produced by PTECs when stimulated with Ephrin B1, but not TGF-β. Thus, there is a canonical EphrinB1/EphB2 as well as a non-canonical EphrinB1/EphB2/TGF-β axis in PTECs that can contribute to inflammation and fibrosis in AKI and its progression to CKD. We hypothesize that EphB2 expressed by PTECs contributes to inflammation and fibrosis following AKI and its progression to CKD by inducing the secretion of MIF and by potentiating TGF-β signaling via phosphorylation of TβRII. In this grant, we will: Determine the contribution of PTECs in EphB2-induced kidney inflammation and fibrosis (Aim 1). Determine the mechanisms whereby EphB2 contributes to inflammation and fibrosis (Aim 2). Determine whether the EphB2 small molecular weight inhibitor is beneficial in AKI and its progression to CKD (Aim 3). This study will identify a novel mechanism whereby EphB2 and TβRII interact; how EphB2/TβRII-mediated fibrotic signaling can be modulated in kidney disease; and devise new therapeutic interventions aimed to prevent EphB2 activation and function in kidney disease.

Up to $866K

2031-01-31

health research

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Grants

Non-canonical EphB2-mediated signaling in AKI and its progression to CKD

Non-Canonical Functions of Polycomb Complexes in Health and Disease

Non-canonical functions of the mitochondrial fission protein Drp1 in ovarian cancer

Non-canonical transcriptional activation of MITF in pigment cells.

Non-canonical translation of pneumovirus mRNAs

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Grants

Non-canonical EphB2-mediated signaling in AKI and its progression to CKD

Non-Canonical Functions of Polycomb Complexes in Health and Disease

Non-canonical functions of the mitochondrial fission protein Drp1 in ovarian cancer

Non-canonical transcriptional activation of MITF in pigment cells.

Non-canonical translation of pneumovirus mRNAs

Non-coding RNAs and chronic limb threatening ischemia

Non-Infectious VZV EVs as a novel modulator of HSV-1 Neurovirulence

Non-invasive close to real-time assessment of dynamic pupil responses to different light stimuli and the relationship between those pupil responses and circadian rhythm and sleep metrics

Non-Invasive Methods for Diagnosis and Progression of Diabetes, Kidney, Urological, Hematological and Digestive Diseases (R01)

Non-invasive Modulation of Microglia Gene Expression Using Peripherally Administered Antibody Conjugates

Non-Invasive Single-Cell Morphometry and Tracking in Living Bacterial Biofilms

Non-Invasive Vagus Nerve Stimulation in Subarachnoid Hemorrhage

Non-Native Invasive Species (NNIS) Mastication – NRV Ranger District

Non-Personal Healthcare Services-Physicians & Other Professional Ambulatory Services for PRC Program

Non-siderophore function of peroxisomes in Histoplasma pathogenesis

NON-TARGET MARKET LABOR CONSULTATION AND REPRESENTATION SERVICES - 10000186633

Non-thematic actions targeting disruptive technologies for defence

Non-thematic development actions by SMEs

Non-thematic research actions by SMEs and research organisations

Nonhighway and Off-Road Vehicle Activities Program - Education and Enforcement

Nonhighway and Off-Road Vehicle Activities Program - Education and Enforcement

Nonhighway and Off-Road Vehicle Activities Program - Nonhighway Road

Nonhighway and Off-Road Vehicle Activities Program - Nonhighway Road

Nonhighway and Off-Road Vehicle Activities Program - Nonmotorized