Ascending vasa recta are angiopoietin/Tie2-dependent lymphatic-like vessels

Yael Kenig-Kozlovsky, Rizaldy P. Scott, Tuncer Onay, Isabel Anna Carota, Benjamin R. Thomson, Hyea Jin Gil, Veronica Ramirez, Shinji Yamaguchi, Christine E. Tanna, Stefan Heinen, Christine Wu, Radu V. Stan, Janet D. Klein, Jeff M. Sands, Guillermo Oliver, Susan E. Quaggin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed fromthe loop of Henle and collecting ducts. Inmost tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle-associated protein). Taken together, our data redefine the AVRs as Tie2 signaling-dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.

Original languageEnglish (US)
Pages (from-to)1097-1107
Number of pages11
JournalJournal of the American Society of Nephrology
Issue number4
StatePublished - Apr 2018

ASJC Scopus subject areas

  • Nephrology


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