Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury

David P. Basile, Jessica L. Friedrich, Jasmina Spahic, Nicole Knipe, Henry Mang, Ellen C. Leonard, Saeed Changizi-Ashtiyani, Robert L. Bacallao, Bruce A. Molitoris, Timothy A. Sutton

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180 Scopus citations

Abstract

Acute kidney injury induces the loss of renal microvessels, but the fate of endothelial cells and the mechanism of potential vascular endothelial growth factor (VEGF)-mediated protection is unknown. Cumulative cell proliferation was analyzed in the kidney of Sprague-Dawley rats following ischemia-reperfusion (I/R) injury by repetitive administration of BrdU (twice daily) and colocalization in endothelial cells with CD31 or cablin. Proliferating endothelial cells were undetectable for up to 2 days following I/R and accounted for only ~1% of BrdU-positive cells after 7 days. VEGF-121 preserved vascular loss following I/R but did not affect proliferation of endothelial, perivascular cells or tubular cells. Endothelial mesenchymal transition states were identified by localizing endothelial markers (CD31, cablin, or infused tomato lectin) with the fibroblast marker S100A4. Such structures were prominent within 6 h and sustained for at least 7 days following I/R. A Tie-2-cre transgenic crossed with a yellow fluorescent protein (YFP) reporter mouse was used to trace the fate of endothelial cells and demonstrated interstititial expansion of YFP-positive cells colo-calizing with S100A4 and smooth muscle actin following I/R. The interstitial expansion of YFP cells was attenuated by VEGF-121. Multiphoton imaging of transgenic mice revealed the alteration of YFP-positive vascular cells associated with blood vessels characterized by limited perfusion in vivo. Taken together, these data indicate that vascular dropout post-AKI results from endothelial phenotypic transition combined with an impaired regenerative capacity, which may contribute to progressive chronic kidney disease.

Original languageEnglish (US)
Pages (from-to)F721-F733
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 1 2011

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Keywords

  • Capillary
  • Fibroblast
  • Fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

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