Dysmorphogenesis of kidney cortical peritubular capillaries in angiopoietin-2-deficient mice.
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, alpha smooth muscle actin (alpha SMA), platelet-derived growth factor receptor beta (PDGFR beta), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, alpha SMA, desmin, and PDGFR beta prominently immunolocalized in cortical peritubular locations. Some alpha SMA-positive cells were closely associated with CD31- and Tie-2-positive peritubular capillary endothelia, and some of the alpha SMA-positive cells expressed PDGFR beta, 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.
Pitera
Jolanta E
JE
Institute of Child Health, University College London, London, UK.
Woolf
Adrian S
AS
Gale
Nicholas W
NW
Yancopoulos
George D
GD
Yuan
Hai Tao
HT
D042702:Angiopoietin-2 / Q000172:deficiency*; D000818:Animals; D002196:Capillaries / Q000002:abnormalities*; D003893:Desmin / Q000378:metabolism; D007672:Kidney Cortex / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009130:Muscle, Smooth / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism; D012079:Renal Circulation; D014443:Tyrosine / Q000378:metabolism
D042702:Angiopoietin-2; D003893:Desmin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014443:Tyrosine; D020797:Receptor, Platelet-Derived Growth Factor beta; D042787:Receptor, TIE-2