Podocyte EphB4 signaling helps recovery from glomerular injury

Wnuk, Monika; Hlushchuk, Ruslan; Janot, Mathilde; Tuffin, Gérald; Martiny-Baron, Georg; Holzer, Philipp; Imbach‐Weese, Patricia; Djonov, Valentin; Huynh‐Do, Uyen

doi:10.1038/ki.2012.17

Cited by 28 publications

(23 citation statements)

References 49 publications

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“…Initial research on ephrin/Eph focused on embryonic tissue patterning and, subsequently, on adult organ pathologies, including malignancies, tissue injury, inflammation, and wound healing (80,112,165,178,222,254,255,260,331,344). In the brain, EphA7, which is present in ependymal cells and astrocytes, induces reverse signaling in progenitor cells and neuroblasts expressing A2, attenuating the formation of neurons in the olfactory bulb (138).…”

Section: Cpc Migration and The Ephrin/eph Receptor Systemmentioning

confidence: 99%

Aging Effects on Cardiac Progenitor Cell Physiology

Rota

Goichberg

Anversa

et al. 2015

Comprehensive Physiology

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Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy.

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Section: Cpc Migration and The Ephrin/eph Receptor Systemmentioning

confidence: 99%

Aging Effects on Cardiac Progenitor Cell Physiology

Rota

Goichberg

Anversa

et al. 2015

Comprehensive Physiology

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“…To block EphB4 forward signaling, we used NVP-BHG712, a novel small molecular weight inhibitor designed to block EphB4 phosphorylation (Novartis Institutes for BioMedical Research, Basel, Switzerland). Successful blocking was previously determined by evaluation of EphB4 phosphorylation, and the effective dose was 50-100 mg/kg [34]. Bioactivity of ephrinB2 was neutralized with anti-ephrinB2 antibody (Neuromics, Edina, MN 55439), and presence of the protein was detected by immunohistochemistry.…”

Section: Reagentsmentioning

confidence: 99%

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

et al. 2013

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Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/ intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in upregulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.

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“…Additionally, ephrinB1 is found throughout the nephron where its interactions with its corresponding receptors EphB2 and EphB6 modulate filtration through changes of the actin cytoskeleton in tubular cells [9]. In adult rat kidneys, our laboratory recently demonstrated the central role of EphB4 in intussusceptive angiogenesis and podocyte recovery from injury [10]. Furthermore, several studies have addressed the role of EphA2 in kidney recovery.…”

Section: Introductionmentioning

confidence: 97%

Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury

Rodriguez

Rudloff

Koenig

et al. 2016

Pflugers Arch - Eur J Physiol

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Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular cell attachment, (ii) secretion of basal membrane proteins and (iii) EPO production. These findings could thus pave the way to new therapeutic approaches.

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Podocyte EphB4 signaling helps recovery from glomerular injury

Cited by 28 publications

References 49 publications

Aging Effects on Cardiac Progenitor Cell Physiology

Aging Effects on Cardiac Progenitor Cell Physiology

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury

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