Tubular Vascular Endothelial Growth Factor-A, Erythropoietin, and Medullary Vessels
Authors: Alda Tufro
Journal: Journal of the American Society of Nephrology (2014)

The complex architecture of the renal vasculature is essential for the organ function and comprises three capillary beds.1,2 Glomerular capillaries are flanked by high-resistance afferent and efferent arterioles. Two postglomerular capillary networks emerge in series from efferent arterioles. Efferent arterioles from superficial glomeruli give rise to cortical peritubular capillaries, whereas those from juxtamedullary glomeruli give rise to vasa recta. Close alignment of the postglomerular microvasculature with cortical and medullary renal tubules is critical for O2 delivery to all nephron segments and for fluid and solute reabsorption from them. Development of postglomerular capillary beds is thought to be driven and regulated by an array of angiogenic factors secreted by renal tubules and endothelial or mural cell precursors, including vascular endothelial growth factor-A (VEGF-A), angiopoietins, stromal cell–derived factor-1, erythropoietin (EPO), and angiotensin II. Although the expression pattern and function of these factors is well known, their specific role in the establishment and homeostasis of the renal medullary vessels is not clear.2 In this issue of JASN, Dimke et al.3 examined the role of renal tubular VEGF-A in vivo using doxycycline-regulated, tubular-specific VEGF-A deletion (VEGFtub) during development and in adult mice, combined with reporter mice. These elegant studies revealed that tubular VEGF-A is necessary during development to establish medullary microvessels and to reach normal kidney size. Loss of tubular VEGF-A after weaning impairs the maintenance of medullary microvasculature. In addition, loss of tubular VEGF-A leads to EPO induction resulting in polycythemia. Interestingly, VEGFtub kidneys were smaller but normal histologically and functionally, in terms of fluid and electrolyte handling as well as BP regulation. Circulating VEGF-A levels were not different in VEGFtub and control mice. Thus, reduced VEGFtub kidney weight (mostly tubular mass) implies a autocrine VEGF-A requirement for tubular growth, consistent with data showing that VEGF-A promotes tubulogenesis and renal tubular cell proliferation.4–6 Similarly, decreased VEGFtub medullary microvasculature development demonstrates a paracrine VEGF-A requirement for peritubular capillary growth and alignment. Together, these findings suggest that VEGFtub mice developed compensatory mechanisms to match the vascular supply to metabolic needs of the smaller tubular mass. The drastic renal and circulating EPO increase observed in VEGFtub mice documents hypoxia in the renal medulla. Hypoxia due to either decreased pO2 or lack of O2 transport capacity (anemia) leads to stabilization of HIF-1α, a transcriptional activator of hypoxia-inducible genes, including EPO, nitric oxide synthase (NOS), VEGF-A, and other angiogenic factors (angiopoietin-1, angiopoietin-2, PDGFBB, FGFb, angiopoietin-L4), which are expressed in the kidney.7 Despite loss of tubular VEGF-A, the collective hypoxia response restored homeostasis (i.e., normal renal histology, function, and BP) in VEGFtub mice, albeit at the expense of significant polycythemia. EPO regulation by hypoxia mediated by HIF-1α induces EPO transcription and translation.7,8 In addition to endocrine stimulation of erythropoiesis, EPO promotes endothelial cell survival and proliferation in vitro and in vivo.9,10 Like VEGFtub mice, Epo transgenic mice develop hematocrit of approximately 80%, have normal BP and renal function, and have no evidence of cardiovascular disease or thrombotic events. This remarkable adaptation was found to be mediated by increased endothelial NOS (eNOS) expression and nitric oxide (NO) levels.11 It appears likely that these mechanisms are involved in VEGFtub mice phenotype as well. Endogenous NO generated in response to hypoxia is known to play an important role in the homeostasis of the oxygen supply to the renal medulla and to prevent hypoxic injury.12 Moreover, intrinsic NO and reactive oxygen species (ROS) regulate descending vasa recta contraction, whereby inhibition of NOS with Nω-nitro-L-arginine methyl ester (L-NAME) constricts descending vasa recta, an effect that is abrogated by NO donors or cGMP and blunted by NAPDH inhibitor and superoxide dismutase mimetics.13 These findings suggest that NO/SNO donors might mitigate the peritubular capillary dropout in VEGFtub mice. Other factors may also be involved in VEGFtub phenotype. Although angiopoietin-1 contributes to the angiogenic response to hypoxia, angiopoietin-2 leads to vessel regression in the absence of VEGF-A.14 The developmental VEGFtub phenotype in the renal medulla is remarkably similar to that induced by an angiotensin II type 1 antagonist in neonatal rats, which downregulates VEGF-A, angiopoietin-1, angiopoietin-2, and the tie-2 receptor, suggesting that angiotensin II/AT1A signaling promotes expansion of postglomerular capillary through several angiogenic factors.15 Proliferation of SMA+ cells along with renal EPO producing cells in the interstitium of VEGFtub occurred only after an approximately 20% drop in hematocrit, suggesting that this fibrosis-like response is EPO independent (EPO mRNA change is similar to C57 controls), and may involve increased PDGF receptor (PDGFR) signaling, known to be induced by acute hypoxia and to cause myofibroblast proliferation (SMA+/PDGFRβ+ cells).16 Further studies are needed to evaluate whether this process is reversible or leads to fibrosis and CKD, as reported in unilateral ureteral obstruction.17 The report by Dimke et al.3 represents an exciting contribution to understanding the role of tubular VEGF in kidney development and disease pathogenesis. Furthermore, this study demonstrates that tubular VEGF-A is necessary for full development of the renal medulla, and loss of tubular VEGF-A elicits a homeostatic response to regional hypoxia involving EPO, resulting in mild microvascular dropout in the mature kidney with no functional abnormalities. Additional work will be necessary to ascertain the mechanistic links among VEGF-A signaling, hypoxia/anemia, and renal fibrosis in humans. This study raises appealing questions to be addressed in futures studies: Are there tubular VEGF-independent mechanisms that guide peritubular capillary development in the cortex? Do medullary microvessels from VEGFtub mice lack endothelial cell fenestrations, as observed in mice treated with VEGF receptor 2 kinase inhibitors?18 Elucidation of the role of NO, eNOS, and ROS in the adaptive hypoxia response observed in this model may uncover novel therapeutic targets and set the stage for translational research. Disclosures None. This work was supported by grants from the National Institutes of Health (R01-DK059333 and R01-DK098824).