Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney.
Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries. Embryonic deletion of tubular Vegfa did not affect systemic Vegfa levels, whereas renal Vegfa abundance was markedly decreased. Excision of Vegfa from renal tubules resulted in the formation of a smaller kidney, with a striking reduction in the density of peritubular capillaries. Consequently, elimination of tubular Vegfa caused pronounced polycythemia because of increased renal erythropoietin (Epo) production. Reducing hematocrit to normal levels in tubular Vegfa-deficient mice resulted in a markedly augmented renal Epo production, comparable with that observed in anemic wild-type mice. Here, we show that tubulovascular cross-talk by Vegfa is essential for maintenance of peritubular capillary networks in kidney. Disruption of this communication leads to increased renal Epo production and resulting polycythemia, presumably to counterbalance microvascular losses.
The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark; Department of Biomedicine, University of Aarhus, Aarhus, Denmark;
Henrik
H
Dimke
Division of Nephrology and Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina; and.
Matthew A
MA
Sparks
Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois;
Benjamin R
BR
Thomson
Department of Biomedicine, University of Aarhus, Aarhus, Denmark;
Sebastian
S
Frische
Division of Nephrology and Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina; and Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Thomas M
TM
Coffman
The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois; quaggin@northwestern.edu.
Susan E
SE
Quaggin
D000818:Animals; D001794:Blood Pressure; D004573:Electrolytes / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D006400:Hematocrit; D007684:Kidney Tubules / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels; D011086:Polycythemia; D020239:Receptor Cross-Talk; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004573:Electrolytes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004921:Erythropoietin
endothelial growth factor inhibition; erythropoietin; kidney; peritubular capillary rarefaction; polycythemia; vascular