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(American Journal of Pathology. 2004;165:1895-1906.)
© 2004 American Society for Investigative Pathology

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

Jolanta E. Pitera^*, Adrian S. Woolf^*, Nicholas W. Gale, George D. Yancopoulos and Hai Tao Yuan^*

From the Institute of Child Health,^* University College London, London, United Kingdom; Regeneron Pharmaceuticals Inc, Tarrytown, New York; and Harvard Medical School, Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Angiopoietin-2 (Ang-2) modulates Tie-2 receptor activation. In mouse kidney maturation, Ang-2 is expressed in arteries, with lower levels in tubules, whereas Tie-2 is expressed by endothelia. We hypothesized that Ang-2 deficiency disrupts kidney vessel patterning. The normal renal cortical peritubular space contains fenestrated capillaries, which have few pericytes; they receive water and solutes which proximal tubules reclaim from the glomerular filtrate. In wild-type neonates, smooth muscle actin (SMA), platelet-derived growth factor receptor ß (PDGFRß), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, SMA, desmin, and PDGFRß prominently immunolocalized in cortical peritubular locations. Some SMA-positive cells were closely associated with CD31- and Tie-2-positive peritubular capillary endothelia, and some of the SMA-positive cells expressed PDGFRß, desmin, and neural/glial cell 2 (NG2), consistent with a pericyte-like identity. Immunoblotting suggested an increase of total and tyrosine-phosphorylated Tie-2 proteins in null mutant versus wild-type kidneys, and electron microscopy confirmed disorganized capillaries and adjacent cells in cortical peritubular spaces in mutant neonate kidneys. Hence, Ang-2 deficiency causes dysmorphogenesis of cortical peritubular capillaries, with adjacent cells expressing pericyte-like markers; we speculate the latter effect is caused by disturbed paracrine signaling between endothelial and surrounding mesenchymal precursor cells.

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