Abstract
Vascular endothelial growth factor C (VEGF‐C) is an angiogenic and lymphangiogenic growth factor. Recent research has revealed the role for VEGF‐C in regulating autophagy by interacting with a nontyrosine kinase receptor, neuropilin‐2 (NRP–2). However, whether VEGF‐C participates in regulating cell survival and autophagy in renal proximal tubular cells is unknown. To address this question, we employed a cell modal of serum deprivation to verify the role of VEGF‐C and its receptor NRP–2 in regulating cell survival and autophagy in NRK52E cell lines. The results show that VEGF‐C rescued the loss of cell viability induced by serum deprivation in a concentration‐dependent manner. Furthermore, endogenous VEGF‐C was knocked down in NRK52E cells by using specific small‐interfering RNAs (siRNA), cells were more sensitive to serum deprivation–induced cell death. A similar increase in cell death rate was observed following NRP–2 depletion in serum‐starved NRK52E cells. Autophagy activity in serum‐starved NRK52E cells was confirmed by western blot analysis of microtubule‐associated protein‐1 chain 3 (LC3), immunofluorescence staining of endogenous LC3, and the formation of autophagosomes by electron microscopy. VEGF‐C or NRP–2 depletion further increased LC3 expression induced by serum deprivation, suggesting that VEGF‐C and NRP–2 were involved in controlling autophagy in NRK52E cells. We further performed autophagic flux experiments to identify that VEGF‐C promotes the activation of autophagy in serum‐starved NRK52E cells. Together, these results suggest for the first time that VEGF‐C/NRP–2 axis promotes survival and autophagy in NRK52E cells under serum deprivation condition.Significance of the studyMore researchers had focused on the regulation of autophagy in kidney disease. The effect of VEGF‐C on cell death and autophagy in renal epithelial cells has not been examined. We first identified the VEGF‐C as a regulator of cell survival and autophagy in NRK52E cell lines. And VEGF‐C/NRP–2 may mediate autophagy by regulating the phosphorylation of 4EBP1 and P70S6K. VEGF‐C treatment may be identified as a therapeutic target in renal injury repair due to its capacity to promote tubular cell survival in the future.
Highlights
Tubular cell injury and death are the major lesion of kidney damage caused by ischemia reperfusion injury and nephrotoxicity injury
This study was undertaken to illuminate the role of Vascular endothelial growth factor C (VEGF‐C) and its receptor NRP–2 in regulating renal tubular epithelial cell survival and autophagy
VEGF‐C was identified as a key lymphangiogenic factor, mainly acting via VEGF receptor (VEGFR)‐3.28 Numerous studies have shown that VEGF‐C promoted tumour metastasis in various malignancies by mediating tumour angiogenesis, lymphangiogenesis, and invasion.[29,30]
Summary
Tubular cell injury and death are the major lesion of kidney damage caused by ischemia reperfusion injury and nephrotoxicity injury. Neuropilins are single‐pass transmembrane, non‐tyrosine kinase receptors, including two homologous members NRP–1 and NRP–2.13 As coreceptors for VEGF receptors or Plexins, neuropilins bind different members of the semaphorin family and VEGF family[14,15] and play essential roles in axonal guidance, angiogenesis, lymphangiogenesis, and tumour progression.[13] They are mainly expressed in neuronal tissues, several muscles, kidney, lung, some immune cells, various cancer tissue, and cancer cell lines.[14,16,17] Studies have confirmed that NRP– 2 expression is associated with metastasis and a poor prognosis in a great majority of tumours.[18,19,20,21] In kidney, increased tubular and interstitial NRP–2 expression was observed in renal biopsy tissues from FSGS patients with various degrees of tubulointerstitial fibrosis.[22] Upregulation of NRP–2 mRNA in kidney biopsies from patients with nephritic kidney diseases is correlated with worsening renal function and poor renal prognosis.[22]. Our findings demonstrate that VEGF‐C and NRP2 participate in promoting survival and regulating autophagy in renal epithelial cells under serum deprivation condition
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