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Abstract: SA-PO243

High Glucose Stimulates Basolateral Secretion of Semaphorin 3G by Proximal Tubule Cells: Role in Anti-Angiogenesis

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Caceres, Paulo S., Henry Ford Health System, Detroit, Michigan, United States

Hyperglycemia in the diabetic kidney causes tubular and microvascular abnormalities that eventually lead to kidney damage. Given the close association between the proximal tubule and peritubular capillaries, a thorough understanding of their interaction could help identify mechanisms of diabetic kidney disease. Microvascular abnormalities are known to occur in diabetic patients and animal models. Despite known growth factors produced by the proximal tubule that could potentially target neighboring endothelial cells, it is not well understood whether the proximal tubule regulates angiogenesis. Here we propose that proximal tubule secretes Semaphorin-3G (Sema3G), an anti-angiogenic protein. We hypothesize, that high glucose stimulates Sema3G secretion by proximal tubule cells and inhibits angiogenesis.


We utilized co-cultures of RPTEC proximal tubule and HUVEC endothelial cell lines. We analyzed angiogenesis via tubulogenesis assays in Matrigel and cell migration via wound-healing assays. We assessed kidney angiogenesis in primary cultures of mouse kidney endothelial cells and sprouting angiogenesis in cortex explants from diabetic Akita mice.


We observed decreased sprouting angiogenesis (baseline and VEGF-stimulated) in kidney cortex explants of diabetic Akita mice vs. C57BL counterparts. To identify a potential proximal tubule anti-angiogenic factor, we measured release of Sema3G from polarized RPTEC cells. We found that RPTEC cells secreted Sema3G basolaterally and this was stimulated by high glucose (25 mM). Conversely, RPTEC cells pre-grown on high glucose lost their ability to stimulate angiogenesis in co-cultured HUVEC endothelial cells. When we administered recombinant Sema3G to endothelial cells in culture, we found that Sema3G had little effect in baseline angiogenesis, but it inhibited VEGF-stimulated angiogenesis in HUVEC and primary culture of kidney endothelial cells. Finally, when we silenced the semaphorin receptor Plexin-D1 via shRNAs in endothelial cells, we observed accelerated cell migration in the absence or presence of co-cultured RPTEC cells, confirming the inhibitory role of semaphorin signaling in endothelial cells.


We conclude that RPTEC proximal tubule cells secrete Sema3G, which is stimulated by high glucose, and this anti-angiogenic factor inhibits angiogenesis in HUVEC and mouse kidney endothelial cells.


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