Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1989 Aug;135(2):261–269.

Regulation of mesangial cell growth by polypeptide mitogens. Inhibitory role of transforming growth factor beta.

F Jaffer 1, C Saunders 1, P Shultz 1, D Throckmorton 1, E Weinshell 1, H E Abboud 1
PMCID: PMC1879918  PMID: 2782372

Abstract

Proliferation of mesangial cells is a common histologic abnormality in glomerular diseases. In vivo studies suggest a role for platelets and monocytes-macrophages in mediating glomerular hypercellularity. The authors recently reported that several peptide growth factors stimulate DNA synthesis and growth of human mesangial cells. This article reports that transforming growth factor beta (TGF-beta), a peptide released by inflammatory cells and platelets, inhibits DNA synthesis and growth of human mesangial cells. The stimulatory and inhibitory effects of these mitogens on DNA synthesis and growth was confirmed by autoradiography and cell counting. The inhibitory effect of TGF-beta is not mediated at the receptor level because TGF-beta did not inhibit the binding of epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) to mesangial cells. Because peptide growth factors that stimulate DNA synthesis in mesangial cells induce expression of PDGF mRNAs, the effect of TGF-beta on PDGF mRNAs expression induced by peptide growth factors was studied. TGF-beta did not lower the increased levels of PDGF mRNAs caused by EGF or PDGF. These data show that TGF-beta is a potent inhibitor of DNA synthesis and growth of mesangial cells. The mechanism of the inhibitory effect of TGF-beta remains to be determined.

Full text

PDF
267

Images in this article

266Figure 5
on p.266
266Figure 7
on p.266
267Figure 8
on p.267

Selected References

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

  1. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Assoian R. K., Frolik C. A., Roberts A. B., Miller D. M., Sporn M. B. Transforming growth factor-beta controls receptor levels for epidermal growth factor in NRK fibroblasts. Cell. 1984 Jan;36(1):35–41. doi: 10.1016/0092-8674(84)90071-0. [DOI] [PubMed] [Google Scholar]
  3. Assoian R. K., Grotendorst G. R., Miller D. M., Sporn M. B. Cellular transformation by coordinated action of three peptide growth factors from human platelets. 1984 Jun 28-Jul 4Nature. 309(5971):804–806. doi: 10.1038/309804a0. [DOI] [PubMed] [Google Scholar]
  4. Assoian R. K., Komoriya A., Meyers C. A., Miller D. M., Sporn M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983 Jun 10;258(11):7155–7160. [PubMed] [Google Scholar]
  5. Betsholtz C., Johnsson A., Heldin C. H., Westermark B., Lind P., Urdea M. S., Eddy R., Shows T. B., Philpott K., Mellor A. L. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature. 1986 Apr 24;320(6064):695–699. doi: 10.1038/320695a0. [DOI] [PubMed] [Google Scholar]
  6. Beutler B., Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987 Feb 12;316(7):379–385. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
  7. Cameron J. S. Platelets in glomerular disease. Annu Rev Med. 1984;35:175–180. doi: 10.1146/annurev.me.35.020184.001135. [DOI] [PubMed] [Google Scholar]
  8. Carr B. I., Hayashi I., Branum E. L., Moses H. L. Inhibition of DNA synthesis in rat hepatocytes by platelet-derived type beta transforming growth factor. Cancer Res. 1986 May;46(5):2330–2334. [PubMed] [Google Scholar]
  9. Cotran R. S. Monocytes, proliferation, and glomerulonephritis. J Lab Clin Med. 1978 Dec;92(6):837–840. [PubMed] [Google Scholar]
  10. Daniel T. O., Gibbs V. C., Milfay D. F., Garovoy M. R., Williams L. T. Thrombin stimulates c-sis gene expression in microvascular endothelial cells. J Biol Chem. 1986 Jul 25;261(21):9579–9582. [PubMed] [Google Scholar]
  11. Derynck R., Jarrett J. A., Chen E. Y., Eaton D. H., Bell J. R., Assoian R. K., Roberts A. B., Sporn M. B., Goeddel D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. doi: 10.1038/316701a0. [DOI] [PubMed] [Google Scholar]
  12. Donadio J. V., Jr, Anderson C. F., Mitchell J. C., 3rd, Holley K. E., Ilstrup D. M., Fuster V., Chesebro J. H. Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy. N Engl J Med. 1984 May 31;310(22):1421–1426. doi: 10.1056/NEJM198405313102203. [DOI] [PubMed] [Google Scholar]
  13. Dubois C. H., Foidart J. B., Hautier M. B., Dechenne C. A., Lemaire M. J., Mahieu P. R. Proliferative glomerulonephritis in rats: evidence that mononuclear phagocytes infiltrating the glomeruli stimulate the proliferation of endothelial and mesangial cells. Eur J Clin Invest. 1981 Apr;11(2 Suppl 1):91–104. doi: 10.1111/j.1365-2362.1981.tb02045.x. [DOI] [PubMed] [Google Scholar]
  14. Hammacher A., Hellman U., Johnsson A., Ostman A., Gunnarsson K., Westermark B., Wasteson A., Heldin C. H. A major part of platelet-derived growth factor purified from human platelets is a heterodimer of one A and one B chain. J Biol Chem. 1988 Nov 5;263(31):16493–16498. [PubMed] [Google Scholar]
  15. Heimark R. L., Twardzik D. R., Schwartz S. M. Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. Science. 1986 Sep 5;233(4768):1078–1080. doi: 10.1126/science.3461562. [DOI] [PubMed] [Google Scholar]
  16. Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
  17. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Klahr S., Schreiner G., Ichikawa I. The progression of renal disease. N Engl J Med. 1988 Jun 23;318(25):1657–1666. doi: 10.1056/NEJM198806233182505. [DOI] [PubMed] [Google Scholar]
  19. Like B., Massagué J. The antiproliferative effect of type beta transforming growth factor occurs at a level distal from receptors for growth-activating factors. J Biol Chem. 1986 Oct 15;261(29):13426–13429. [PubMed] [Google Scholar]
  20. Lovett D. H., Sterzel R. B. Cell culture approaches to the analysis of glomerular inflammation. Kidney Int. 1986 Aug;30(2):246–254. doi: 10.1038/ki.1986.176. [DOI] [PubMed] [Google Scholar]
  21. MacCarthy E. P., Hsu A., Ooi Y. M., Ooi B. S. Modulation of mouse mesangial cell proliferation by macrophage products. Immunology. 1985 Dec;56(4):695–699. [PMC free article] [PubMed] [Google Scholar]
  22. Menè P., Abboud H. E., Dubyak G. R., Scarpa A., Dunn M. J. Effects of PDGF on inositol phosphates, Ca2+, and contraction of mesangial cells. Am J Physiol. 1987 Sep;253(3 Pt 2):F458–F463. doi: 10.1152/ajprenal.1987.253.3.F458. [DOI] [PubMed] [Google Scholar]
  23. Oka Y., Orth D. N. Human plasma epidermal growth factor/beta-urogastrone is associated with blood platelets. J Clin Invest. 1983 Jul;72(1):249–259. doi: 10.1172/JCI110964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Palombella V. J., Mendelsohn J., Vilcek J. Mitogenic action of tumor necrosis factor in human fibroblasts: interaction with epidermal growth factor and platelet-derived growth factor. J Cell Physiol. 1988 Apr;135(1):23–31. doi: 10.1002/jcp.1041350104. [DOI] [PubMed] [Google Scholar]
  25. Palombella V. J., Yamashiro D. J., Maxfield F. R., Decker S. J., Vilcek J. Tumor necrosis factor increases the number of epidermal growth factor receptors on human fibroblasts. J Biol Chem. 1987 Feb 15;262(5):1950–1954. [PubMed] [Google Scholar]
  26. Rall L. B., Scott J., Bell G. I., Crawford R. J., Penschow J. D., Niall H. D., Coghlan J. P. Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature. 1985 Jan 17;313(5999):228–231. doi: 10.1038/313228a0. [DOI] [PubMed] [Google Scholar]
  27. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  28. Roberts A. B., Anzano M. A., Meyers C. A., Wideman J., Blacher R., Pan Y. C., Stein S., Lehrman S. R., Smith J. M., Lamb L. C. Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry. 1983 Dec 6;22(25):5692–5698. doi: 10.1021/bi00294a002. [DOI] [PubMed] [Google Scholar]
  29. Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rossi P., Karsenty G., Roberts A. B., Roche N. S., Sporn M. B., de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. doi: 10.1016/s0092-8674(88)80033-3. [DOI] [PubMed] [Google Scholar]
  31. Schreiner G. F., Cotran R. S., Pardo V., Unanue E. R. A mononuclear cell component in experimental immunological glomerulonephritis. J Exp Med. 1978 Feb 1;147(2):369–384. doi: 10.1084/jem.147.2.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
  33. Shultz P. J., DiCorleto P. E., Silver B. J., Abboud H. E. Mesangial cells express PDGF mRNAs and proliferate in response to PDGF. Am J Physiol. 1988 Oct;255(4 Pt 2):F674–F684. doi: 10.1152/ajprenal.1988.255.4.F674. [DOI] [PubMed] [Google Scholar]
  34. Silver B. J., Jaffer F. E., Abboud H. E. Platelet-derived growth factor synthesis in mesangial cells: induction by multiple peptide mitogens. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1056–1060. doi: 10.1073/pnas.86.3.1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sporn M. B., Roberts A. B. Peptide growth factors and inflammation, tissue repair, and cancer. J Clin Invest. 1986 Aug;78(2):329–332. doi: 10.1172/JCI112580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  37. Sporn M. B., Roberts A. B., Wakefield L. M., de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. doi: 10.1083/jcb.105.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stein G. H., Yanishevsky R. Autoradiography. Methods Enzymol. 1979;58:279–292. doi: 10.1016/s0076-6879(79)58143-9. [DOI] [PubMed] [Google Scholar]
  39. Sterzel R. B., Lovett D. H., Stein H. D., Kashgarian M. The mesangium and glomerulonephritis. Klin Wochenschr. 1982 Sep 15;60(18):1077–1094. doi: 10.1007/BF01715838. [DOI] [PubMed] [Google Scholar]
  40. Sterzel R. B., Pabst R. The temporal relationship between glomerular cell proliferation and monocyte infiltration in experimental glomerulonephritis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1982;38(3):337–350. doi: 10.1007/BF02892829. [DOI] [PubMed] [Google Scholar]
  41. Striker G. E., Lange M. A., MacKay K., Bernstein K., Striker L. J. Glomerular cells in vitro. Adv Nephrol Necker Hosp. 1987;16:169–186. [PubMed] [Google Scholar]
  42. Takehara K., LeRoy E. C., Grotendorst G. R. TGF-beta inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell. 1987 May 8;49(3):415–422. doi: 10.1016/0092-8674(87)90294-7. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES