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

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

Research output: Contribution to journalArticle

70 Scopus citations

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

ASJC Scopus subject areas

  • Nephrology

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