EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury

Yujiro Kida, Nicholas Ieronimakis, Claudia Schrimpf, Morayma Reyes Gil, Jeremy S. Duffield

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidneymicrovascular endothelial cells migrated and proliferated less than wild-typemicrovascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

Original languageEnglish (US)
Pages (from-to)559-572
Number of pages14
JournalJournal of the American Society of Nephrology
Volume24
Issue number4
DOIs
StatePublished - Mar 29 2013
Externally publishedYes

Fingerprint

Pericytes
Fibrosis
Kidney
Wounds and Injuries
Myofibroblasts
EphB4 Receptor
Endothelial Cells
PDZ Domains
Vascular Endothelial Growth Factor Receptor-2
Chronic Renal Insufficiency
Basement Membrane
Vascular Endothelial Growth Factor A
Blood Vessels
Disease Progression
Ligands

ASJC Scopus subject areas

  • Nephrology

Cite this

EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. / Kida, Yujiro; Ieronimakis, Nicholas; Schrimpf, Claudia; Reyes Gil, Morayma; Duffield, Jeremy S.

In: Journal of the American Society of Nephrology, Vol. 24, No. 4, 29.03.2013, p. 559-572.

Research output: Contribution to journalArticle

Kida, Yujiro ; Ieronimakis, Nicholas ; Schrimpf, Claudia ; Reyes Gil, Morayma ; Duffield, Jeremy S. / EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 4. pp. 559-572.
@article{2e65bf87fce74194a9f8964cc34df8b2,
title = "EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury",
abstract = "Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidneymicrovascular endothelial cells migrated and proliferated less than wild-typemicrovascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.",
author = "Yujiro Kida and Nicholas Ieronimakis and Claudia Schrimpf and {Reyes Gil}, Morayma and Duffield, {Jeremy S.}",
year = "2013",
month = "3",
day = "29",
doi = "10.1681/ASN.2012080871",
language = "English (US)",
volume = "24",
pages = "559--572",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "4",

}

TY - JOUR

T1 - EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury

AU - Kida, Yujiro

AU - Ieronimakis, Nicholas

AU - Schrimpf, Claudia

AU - Reyes Gil, Morayma

AU - Duffield, Jeremy S.

PY - 2013/3/29

Y1 - 2013/3/29

N2 - Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidneymicrovascular endothelial cells migrated and proliferated less than wild-typemicrovascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

AB - Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidneymicrovascular endothelial cells migrated and proliferated less than wild-typemicrovascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84875748988&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875748988&partnerID=8YFLogxK

U2 - 10.1681/ASN.2012080871

DO - 10.1681/ASN.2012080871

M3 - Article

C2 - 23492730

AN - SCOPUS:84875748988

VL - 24

SP - 559

EP - 572

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 4

ER -