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. 1999 Mar 1;338(Pt 2):367–374.

Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells.

S Frank 1, B Stallmeyer 1, H Kämpfer 1, C Schaffner 1, J Pfeilschifter 1
PMCID: PMC1220062  PMID: 10024512

Abstract

Under conditions associated with local and systemic inflammation, mesangial cells and invading immune cells are likely to be responsible for the release of large amounts of nitric oxide (NO) in the glomerulus. To further define the mechanisms of NO action in the glomerulus, we attempted to identify genes which are regulated by NO in rat glomerular mesangial cells. We identified vascular endothelial growth factor (VEGF) and its receptor fms-like tyrosine kinase (FLT-1) to be under the regulatory control of exogenously applied NO in these cells. Using S-nitroso-glutathione (GSNO) as an NO-donating agent, VEGF expression was strongly induced, whereas expression of its FLT-1 receptor simultaneously decreased. Expressional regulation of VEGF and FLT-1 mRNA was transient and occurred rapidly within 1-3 h after GSNO treatment. Expression of a second VEGF-specific receptor, fetal liver kinase-1 (FLK-1/KDR), could not be detected. The inflammatory cytokine interleukin-1beta mediated a moderate increase in VEGF expression after 24 h and had no influence on FLT-1 expression. In contrast, platelet-derived growth factor-BB and basic fibroblast growth factor had no effect on VEGF expression, but strongly induced FLT-1 mRNA levels. Obviously, there is a differential regulation of VEGF and its receptor FLT-1 by NO, cytokines and growth factors in rat mesangial cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bacic M., Edwards N. A., Merrill M. J. Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors. 1995;12(1):11–15. doi: 10.3109/08977199509003209. [DOI] [PubMed] [Google Scholar]
  2. Ben-Av P., Crofford L. J., Wilder R. L., Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett. 1995 Sep 18;372(1):83–87. doi: 10.1016/0014-5793(95)00956-a. [DOI] [PubMed] [Google Scholar]
  3. Cattell V., Cook H. T. Nitric oxide: role in the physiology and pathology of the glomerulus. Exp Nephrol. 1993 Sep-Oct;1(5):265–280. [PubMed] [Google Scholar]
  4. Chin K., Kurashima Y., Ogura T., Tajiri H., Yoshida S., Esumi H. Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene. 1997 Jul 24;15(4):437–442. doi: 10.1038/sj.onc.1201201. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Conn G., Bayne M. L., Soderman D. D., Kwok P. W., Sullivan K. A., Palisi T. M., Hope D. A., Thomas K. A. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628–2632. doi: 10.1073/pnas.87.7.2628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
  8. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  9. Frank S., Hübner G., Breier G., Longaker M. T., Greenhalgh D. G., Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem. 1995 May 26;270(21):12607–12613. doi: 10.1074/jbc.270.21.12607. [DOI] [PubMed] [Google Scholar]
  10. Garbers D. L. Guanylyl cyclase receptors and their endocrine, paracrine, and autocrine ligands. Cell. 1992 Oct 2;71(1):1–4. doi: 10.1016/0092-8674(92)90258-e. [DOI] [PubMed] [Google Scholar]
  11. Garrido C., Saule S., Gospodarowicz D. Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. Growth Factors. 1993;8(2):109–117. doi: 10.3109/08977199309046931. [DOI] [PubMed] [Google Scholar]
  12. Garthwaite J., Charles S. L., Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988 Nov 24;336(6197):385–388. doi: 10.1038/336385a0. [DOI] [PubMed] [Google Scholar]
  13. Gruden G., Thomas S., Burt D., Lane S., Chusney G., Sacks S., Viberti G. Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12112–12116. doi: 10.1073/pnas.94.22.12112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Iijima K., Yoshikawa N., Connolly D. T., Nakamura H. Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor. Kidney Int. 1993 Nov;44(5):959–966. doi: 10.1038/ki.1993.337. [DOI] [PubMed] [Google Scholar]
  15. Iruela-Arispe L., Gordon K., Hugo C., Duijvestijn A. M., Claffey K. P., Reilly M., Couser W. G., Alpers C. E., Johnson R. J. Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis. Am J Pathol. 1995 Dec;147(6):1715–1727. [PMC free article] [PubMed] [Google Scholar]
  16. Kashgarian M., Sterzel R. B. The pathobiology of the mesangium. Kidney Int. 1992 Mar;41(3):524–529. doi: 10.1038/ki.1992.74. [DOI] [PubMed] [Google Scholar]
  17. Kitamoto Y., Tokunaga H., Tomita K. Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J Clin Invest. 1997 May 15;99(10):2351–2357. doi: 10.1172/JCI119416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Klanke B., Simon M., Röckl W., Weich H. A., Stolte H., Gröne H. J. Effects of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) on haemodynamics and permselectivity of the isolated perfused rat kidney. Nephrol Dial Transplant. 1998 Apr;13(4):875–885. doi: 10.1093/ndt/13.4.875. [DOI] [PubMed] [Google Scholar]
  19. Knowles R. G., Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298(Pt 2):249–258. doi: 10.1042/bj2980249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kunz D., Mühl H., Walker G., Pfeilschifter J. Two distinct signaling pathways trigger the expression of inducible nitric oxide synthase in rat renal mesangial cells. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5387–5391. doi: 10.1073/pnas.91.12.5387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  22. Li J., Perrella M. A., Tsai J. C., Yet S. F., Hsieh C. M., Yoshizumi M., Patterson C., Endege W. O., Zhou F., Lee M. E. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem. 1995 Jan 6;270(1):308–312. doi: 10.1074/jbc.270.1.308. [DOI] [PubMed] [Google Scholar]
  23. Monacci W. T., Merrill M. J., Oldfield E. H. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol. 1993 Apr;264(4 Pt 1):C995–1002. doi: 10.1152/ajpcell.1993.264.4.C995. [DOI] [PubMed] [Google Scholar]
  24. Mühl H., Pfeilschifter J. Amplification of nitric oxide synthase expression by nitric oxide in interleukin 1 beta-stimulated rat mesangial cells. J Clin Invest. 1995 Apr;95(4):1941–1946. doi: 10.1172/JCI117876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pepper M. S., Ferrara N., Orci L., Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992 Dec 15;189(2):824–831. doi: 10.1016/0006-291x(92)92277-5. [DOI] [PubMed] [Google Scholar]
  26. Pepper M. S., Ferrara N., Orci L., Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun. 1991 Dec 16;181(2):902–906. doi: 10.1016/0006-291x(91)91276-i. [DOI] [PubMed] [Google Scholar]
  27. Pfeilschifter J. Does nitric oxide, an inflammatory mediator of glomerular mesangial cells, have a role in diabetic nephropathy? Kidney Int Suppl. 1995 Sep;51:S50–S60. [PubMed] [Google Scholar]
  28. Pfeilschifter J., Kunz D., Mühl H. Nitric oxide: an inflammatory mediator of glomerular mesangial cells. Nephron. 1993;64(4):518–525. doi: 10.1159/000187394. [DOI] [PubMed] [Google Scholar]
  29. Pfeilschifter J., Rob P., Mülsch A., Fandrey J., Vosbeck K., Busse R. Interleukin 1 beta and tumour necrosis factor alpha induce a macrophage-type of nitric oxide synthase in rat renal mesangial cells. Eur J Biochem. 1992 Jan 15;203(1-2):251–255. doi: 10.1111/j.1432-1033.1992.tb19854.x. [DOI] [PubMed] [Google Scholar]
  30. Pfeilschifter J., Schwarzenbach H. Interleukin 1 and tumor necrosis factor stimulate cGMP formation in rat renal mesangial cells. FEBS Lett. 1990 Oct 29;273(1-2):185–187. doi: 10.1016/0014-5793(90)81080-8. [DOI] [PubMed] [Google Scholar]
  31. Pfeilschifter J., Vosbeck K. Transforming growth factor beta 2 inhibits interleukin 1 beta- and tumour necrosis factor alpha-induction of nitric oxide synthase in rat renal mesangial cells. Biochem Biophys Res Commun. 1991 Mar 15;175(2):372–379. doi: 10.1016/0006-291x(91)91574-v. [DOI] [PubMed] [Google Scholar]
  32. Plüss C., Werner E. R., Blau N., Wachter H., Pfeilschifter J. Interleukin 1 beta and cAMP trigger the expression of GTP cyclohydrolase I in rat renal mesangial cells. Biochem J. 1996 Sep 1;318(Pt 2):665–671. doi: 10.1042/bj3180665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Saura M., López S., Rodríguez Puyol M., Rodríguez Puyol D., Lamas S. Regulation of inducible nitric oxide synthase expression in rat mesangial cells and isolated glomeruli. Kidney Int. 1995 Feb;47(2):500–509. doi: 10.1038/ki.1995.63. [DOI] [PubMed] [Google Scholar]
  34. Schmidt H. H., Lohmann S. M., Walter U. The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta. 1993 Aug 18;1178(2):153–175. doi: 10.1016/0167-4889(93)90006-b. [DOI] [PubMed] [Google Scholar]
  35. Schmidt H. H., Walter U. NO at work. Cell. 1994 Sep 23;78(6):919–925. doi: 10.1016/0092-8674(94)90267-4. [DOI] [PubMed] [Google Scholar]
  36. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  37. Shulman K., Rosen S., Tognazzi K., Manseau E. J., Brown L. F. Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol. 1996 May;7(5):661–666. doi: 10.1681/ASN.V75661. [DOI] [PubMed] [Google Scholar]
  38. Shultz P. J., Archer S. L., Rosenberg M. E. Inducible nitric oxide synthase mRNA and activity in glomerular mesangial cells. Kidney Int. 1994 Sep;46(3):683–689. doi: 10.1038/ki.1994.321. [DOI] [PubMed] [Google Scholar]
  39. Simon M., Röckl W., Hornig C., Gröne E. F., Theis H., Weich H. A., Fuchs E., Yayon A., Gröne H. J. Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites. J Am Soc Nephrol. 1998 Jun;9(6):1032–1044. doi: 10.1681/ASN.V961032. [DOI] [PubMed] [Google Scholar]
  40. Takahashi T., Shirasawa T., Miyake K., Yahagi Y., Maruyama N., Kasahara N., Kawamura T., Matsumura O., Mitarai T., Sakai O. Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells. Biochem Biophys Res Commun. 1995 Apr 6;209(1):218–226. doi: 10.1006/bbrc.1995.1492. [DOI] [PubMed] [Google Scholar]
  41. Thiemermann C. The role of the L-arginine: nitric oxide pathway in circulatory shock. Adv Pharmacol. 1994;28:45–79. doi: 10.1016/s1054-3589(08)60493-7. [DOI] [PubMed] [Google Scholar]
  42. Tsurumi Y., Murohara T., Krasinski K., Chen D., Witzenbichler B., Kearney M., Couffinhal T., Isner J. M. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med. 1997 Aug;3(8):879–886. doi: 10.1038/nm0897-879. [DOI] [PubMed] [Google Scholar]
  43. Uchida K., Uchida S., Nitta K., Yumura W., Marumo F., Nihei H. Glomerular endothelial cells in culture express and secrete vascular endothelial growth factor. Am J Physiol. 1994 Jan;266(1 Pt 2):F81–F88. doi: 10.1152/ajprenal.1994.266.1.F81. [DOI] [PubMed] [Google Scholar]
  44. Unemori E. N., Ferrara N., Bauer E. A., Amento E. P. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol. 1992 Dec;153(3):557–562. doi: 10.1002/jcp.1041530317. [DOI] [PubMed] [Google Scholar]
  45. Wen Y., Edelman J. L., Kang T., Zeng N., Sachs G. Two functional forms of vascular endothelial growth factor receptor-2/Flk-1 mRNA are expressed in normal rat retina. J Biol Chem. 1998 Jan 23;273(4):2090–2097. doi: 10.1074/jbc.273.4.2090. [DOI] [PubMed] [Google Scholar]
  46. Werner S., Peters K. G., Longaker M. T., Fuller-Pace F., Banda M. J., Williams L. T. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6896–6900. doi: 10.1073/pnas.89.15.6896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yamane A., Seetharam L., Yamaguchi S., Gotoh N., Takahashi T., Neufeld G., Shibuya M. A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene. 1994 Sep;9(9):2683–2690. [PubMed] [Google Scholar]

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