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

Abstract

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 ␤ (PDGFR␤), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, ␣SMA, desmin, and PDGFR␤ 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 PDGFR␤, 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.

Roles of Angiopoietins in Kidney Development and Disease

“…41 Ang-2 null mutants die soon after birth with chylous ascites, and neonates display dysmorphogenesis of cortical peritubular capillaries. 42 This observation is consistent with the idea that Ang-2 downregulates Ang-1 signaling in blood endothelia, which themselves then stabilize surrounding smooth muscle cells/pericytes by releasing trophic factors. Indeed, separation of endothelia and supporting cells is a feature of embryos in which either Ang-1 has been deleted 1 or Ang-2 has been overexpressed.…”

“…The effects of downregulating endogenous, glomerular-derived Ang-1 have yet to be published, although, on the basis of the idea that Ang-2 can act as an Ang-1 antagonist, 2 such animals may be found to share several features (e.g., glomerular endothelial apoptosis, albuminuria) of those that overexpress Ang-2 in glomeruli. 43 The observation that Ang-2 is highly expressed in tubules that surround mature vasa rectae, 35 which themselves express Tie-2, 62 suggests that the factor has a special role in patterning and/or maintaining these vessels; however, Ang-2 null mice die neonatally, 42 too soon to be informative for study of mature vasa rectae. Thus, proof of these ideas would require site-specific downregulation of Ang-2.…”

Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

“…The use of pharmacological inhibition of ANG2 by REGN910 circumvented the confounding effects of impaired immune responses, lymphatic defects, and other abnormalities in ANG2 null mice (61)(62)(63)(64). The anti-ANG2 antibody also permitted control over onset, duration, and magnitude of antagonism.…”

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

“…Both pathways have been shown to play crucial roles in postnatal angiogenesis in various organs (Suri et al, 1998;Gerber et al, 1999;Gale et al, 2002;Mattot et al, 2002;Pitera et al, 2004;Ward et al, 2004;Malik et al, 2006;Thurston et al, 2005). VEGF signaling is required for the proliferation and maintenance of newly formed microvasculature, especially in the hepatic sinusoidal vessels during postnatal development and liver regeneration (Gerber et al, 1999;Kraizer et al, 2001;Ross et al, 2001).…”

“…The ANG-TIE2 system might also be involved in the formation of vascular bundles during postnatal kidney development. This is because TIE2 and ANG2 are highly and specifically expressed in the vascular bundles and their associated stromal region of neonatal kidneys, respectively (Yuan et al, 1999;Yuan et al, 2000;Pitera et al, 2004). Although our RNA and immunohistochemical analyses did not show defects in the expression of Tie2 itself in the Sox17 +/--Sox18 -/-mutants, the identification and characterization of target genes will be required to resolve a potential linkage between SOX group F factors and the ANG-TIE2 system in postnatal angiogenesis.…”