VEGF-C promotes survival in podocytes

Abstract

Vascular endothelial growth factor (VEGF)-A is an autocrine survival factor for podocytes, which express two VEGF receptors, VEGF-R1 and VEGF-R3. As VEGF-A is not a known ligand for VEGF-R3, the aim of this investigation was to examine whether VEGF-C, a known ligand for VEGF-R3, served a function in podocyte biology and whether this was VEGF-R3 dependent. VEGF-C protein expression was localized to podocytes in contrast to VEGF-D, which was expressed in parietal epithelial cells. Intracellular calcium ([Ca2+]i) experiments demonstrated that VEGF-C induced a 0.74 ± 0.09-fold reduction in [Ca2+]i compared with baseline in human conditionally immortalized podocytes (hCIPs; P < 0.05, one sample t-test, n = 8). Cytotoxicity experiments revealed that in hCIPs VEGF-C reduced cytotoxicity to 81.4 ± 1.9% of serum-starved conditions ( P < 0.001, paired t-test, n = 16), similar to VEGF-A (82.8 ± 4.5% of serum-starved conditions, P < 0.05, paired t-test). MAZ51 (a VEGF-R3 kinase inhibitor) inhibited the VEGF-C-induced reduction in cytotoxicity (106.2 ± 2.1% of serum-starved conditions), whereas MAZ51 by itself had no cytotoxic effects on hCIPs. VEGF-C was also shown to induce a 0.5 ± 0.13-fold reduction in levels of MAPK phosphorylation compared with VEGF-A and VEGF-A-Mab treatment ( P < 0.05, ANOVA, n = 4), yet had no effect on Akt phosphorylation. Surprisingly, immunoprecipitation studies detected no VEGF-C-induced autophosphorylation of VEGF-R3 in hCIPs but did so in HMVECs. Moreover, SU-5416, a tyrosine kinase inhibitor, blocked the VEGF-C-induced reduction in cytotoxicity (106 ± 2.8% of serum-starved conditions) at concentrations specific for VEGF-R1. Together, these results suggest for the first time that VEGF-C acts in an autocrine manner in cultured podocytes to promote survival, although the receptor or receptor complex activated has yet to be elucidated.

CD2AP/CIN85 Balance Determines Receptor Tyrosine Kinase Signaling Response in Podocytes

“…Particularly in the case of VEGF this is of great interest because this would directly affect paracrine signaling activity via VEGF in podocytes. Depending on recent data, this mechanism is discussed as important for podocyte survival in vitro (21,22). Because these signaling effects were demonstrated for the activation of the PI3K/AKT and the Ras-ERK-MAPK pathway, we confirmed that these two pathways are not dependent on each other.…”

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

“…29 In addition to the protective effects on the renal MV architecture, intrarenal ELP-VEGF therapy improved glomerular expression of podocin, reduced the excretion of nephrin (both major podocyte slit diaphragm-associated proteins 30,31 ), and reduced albuminuria, implying a reduction in podocyte damage. Since podocytes are both targets and sources of VEGF in the kidney, [32][33][34] ELP-VEGF administration may have in turn stimulated a positive feedback mechanism that could have potentiated podocyte production of VEGF and contributed to renoprotection.…”

Nephrotic syndrome unfavorable course correlates with downregulation of podocyte vascular endothelial growth factor receptor (VEGFR)-2

“…Interestingly, VEGF-C could be expressed both in cultured and tissue podocytes. In cultured podocytes, VEGF-C acts in an autocrine manner to promote their survival [10]. In other studies, VEGF-C has been found to increase filtration barrier permeability and has been regarded as a factor of unfavorable prognosis in nephrotic syndrome children [7].…”

“…This apparent discrepancy may be explained by detailed, molecular studies of VEGF-C receptors expressions in filtration barrier elements (podocytes, basement membrane and endothelial cells). Studies performed by Foster et al revealed VEGF-C does not act in cultured podocytes via VEGFR-3 [10]. They concluded that the receptor or receptor complex activated has yet to be elucidated.…”

“…interleukins and VEGF-C) are regarded as playing a fundamental role in this pathomechanism [7,9,10]. Interestingly, VEGF-C could be expressed both in cultured and tissue podocytes.…”