Tubulovascular Cross-Talk by Vascular Endothelial Growth Factor A Maintains Peritubular Microvasculature in Kidney

Abstract

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.

Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

“…Similar to the histologic findings, the reduction in functional vessels assessed by in vivo mCT was observed before the onset of interstitial fibrosis ( Figure 2B). 7,[22][23][24] We confirmed the continuous reduction of vessel functionality in Alport and UUO mice. For both models, in vivo mCT showed significantly reduced rBV values in diseased versus control kidneys ( Figure 5, A and B for UUO; Figure 5, D and E for Alport mice, respectively).…”

“…[1][2][3][4][5][6][7] Several recent studies suggested that restoring the renal microvasculature may provide novel therapeutic options for patients with CKD. [8][9][10][11][12] Thus far, however, quantitative imaging tools allowing for the noninvasive monitoring of morphologic and functional alterations of the renal microvasculature during disease progression have been lacking, and studies investigating vessel rarefaction in CKD have been largely restricted to invasive microscopic end-point analyses.…”

“…[8][9][10][11][12] Thus far, however, quantitative imaging tools allowing for the noninvasive monitoring of morphologic and functional alterations of the renal microvasculature during disease progression have been lacking, and studies investigating vessel rarefaction in CKD have been largely restricted to invasive microscopic end-point analyses. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] We here employed in vivo and ex vivo mCT-based imaging techniques, alongside conventional immunohistochemical methodologies, to demonstrate that (1) contrast-enhanced in vivo mCT imaging is highly suitable for accurate and noninvasive monitoring of vessel functionality during progressive kidney diseases, via quantifying the renal rBV; (2) the renal rBV continuously decreases during early-to-late-stage renal disease progression; (3) vessel functionality is reduced immediately after renal injury prior to the onset of interstitial fibrosis, supporting the assumption that endothelial injury might be a major initiating cause of fibrosis development; and (4) in addition to peritubular capillaries, arterial vessels of virtually all calibers undergo substantial alterations during progressive renal disease with regard to vessel branching, size, and tortuosity.…”

“…In order to exclude model-specific effects related to I/Rinduced progressive kidney injury, the correlation between progressive fibrosis and continuous vessel rarefaction was histologically confirmed in UUO (days [1][2][3][4][5][6][7][8][9][10] and Alport mice (6-8 weeks). Comparable to the time-course findings obtained in the I/R model, a prominent early reduction of Meca-32 positive cortical peritubular capillaries on day 3 also preceded the onset of significant fibrosis, as found on day 5 in the UUO model ( Figure 3A).…”

Tubular Vascular Endothelial Growth Factor-A, Erythropoietin, and Medullary Vessels

“…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 (VEGF tub ) 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.…”