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. 1994 Jul;94(1):50–58. doi: 10.1172/JCI117348

Expression of platelet-derived growth factor receptors in normal and diseased human kidney. An immunohistochemistry and in situ hybridization study.

L Gesualdo 1, S Di Paolo 1, S Milani 1, M Pinzani 1, C Grappone 1, E Ranieri 1, G Pannarale 1, F P Schena 1
PMCID: PMC296281  PMID: 8040291

Abstract

We studied the expression of PDGF-alpha and -beta receptors in 10 normal and 40 pathologic human kidneys (five minimal change disease, five membranous nephropathy, 25 IgA nephropathy, five lupus nephritis), by both immunohistochemistry and in situ hybridization techniques. In normal-appearing kidneys, both PDGF-alpha and -beta receptors were expressed at the glomerular and interstitial level, the latter receptor more intensely than the former. The distribution and degree of expression of both receptors in nonproliferative glomerulonephritides were comparable with those found in normal-appearing kidneys. PDGF-beta receptor gene and protein expression were upregulated in proliferative nephritides both at the glomerular and the interstitial level and strictly correlated with the grade of histologic lesions. Finally, PDGF beta receptor expression was observed at a low level in normal-appearing renal vessels, and strikingly increased in injured arteries. Diseased kidneys displayed only a slight increase of PDGF-alpha receptor expression, chiefly at the interstitial level. Noteworthy, a few cases of lupus nephritis showed a moderate increase of PDGF-alpha receptor also at the glomerular level. These data establish PDGF-beta receptor activation as a candidate for driving glomerular and interstitial proliferation and, probably, expansion of extracellular matrix in proliferative glomerulonephritis, while the role of PDGF-alpha receptor activation at the renal level remains to be elucidated.

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Selected References

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

  1. Abboud H. E. Growth factors in glomerulonephritis. Kidney Int. 1993 Jan;43(1):252–267. doi: 10.1038/ki.1993.39. [DOI] [PubMed] [Google Scholar]
  2. Abboud H. E. Platelet-derived growth factor and mesangial cells. Kidney Int. 1992 Mar;41(3):581–583. doi: 10.1038/ki.1992.86. [DOI] [PubMed] [Google Scholar]
  3. Alpers C. E., Seifert R. A., Hudkins K. L., Johnson R. J., Bowen-Pope D. F. Developmental patterns of PDGF B-chain, PDGF-receptor, and alpha-actin expression in human glomerulogenesis. Kidney Int. 1992 Aug;42(2):390–399. doi: 10.1038/ki.1992.300. [DOI] [PubMed] [Google Scholar]
  4. Alpers C. E., Seifert R. A., Hudkins K. L., Johnson R. J., Bowen-Pope D. F. PDGF-receptor localizes to mesangial, parietal epithelial, and interstitial cells in human and primate kidneys. Kidney Int. 1993 Feb;43(2):286–294. doi: 10.1038/ki.1993.45. [DOI] [PubMed] [Google Scholar]
  5. Battegay E. J., Raines E. W., Seifert R. A., Bowen-Pope D. F., Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell. 1990 Nov 2;63(3):515–524. doi: 10.1016/0092-8674(90)90448-n. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Claesson-Welsh L., Eriksson A., Westermark B., Heldin C. H. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4917–4921. doi: 10.1073/pnas.86.13.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. D'Amico G. Role of interstitial infiltration of leukocytes in glomerular diseases. Nephrol Dial Transplant. 1988;3(5):596–600. doi: 10.1093/oxfordjournals.ndt.a091711. [DOI] [PubMed] [Google Scholar]
  10. Deuel T. F., Senior R. M., Huang J. S., Griffin G. L. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest. 1982 Apr;69(4):1046–1049. doi: 10.1172/JCI110509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eriksson A., Nistér M., Leveen P., Westermark B., Heldin C. H., Claesson-Welsh L. Induction of platelet-derived growth factor alpha- and beta-receptor mRNA and protein by platelet-derived growth factor BB. J Biol Chem. 1991 Nov 5;266(31):21138–21144. [PubMed] [Google Scholar]
  12. Eriksson A., Siegbahn A., Westermark B., Heldin C. H., Claesson-Welsh L. PDGF alpha- and beta-receptors activate unique and common signal transduction pathways. EMBO J. 1992 Feb;11(2):543–550. doi: 10.1002/j.1460-2075.1992.tb05085.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fellström B., Klareskog L., Heldin C. H., Larsson E., Rönnstrand L., Terracio L., Tufveson G., Wahlberg J., Rubin K. Platelet-derived growth factor receptors in the kidney--upregulated expression in inflammation. Kidney Int. 1989 Dec;36(6):1099–1102. doi: 10.1038/ki.1989.306. [DOI] [PubMed] [Google Scholar]
  14. Ferns G. A., Sprugel K. H., Seifert R. A., Bowen-Pope D. F., Kelly J. D., Murray M., Raines E. W., Ross R. Relative platelet-derived growth factor receptor subunit expression determines cell migration to different dimeric forms of PDGF. Growth Factors. 1990;3(4):315–324. doi: 10.3109/08977199009003674. [DOI] [PubMed] [Google Scholar]
  15. Floege J., Burns M. W., Alpers C. E., Yoshimura A., Pritzl P., Gordon K., Seifert R. A., Bowen-Pope D. F., Couser W. G., Johnson R. J. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int. 1992 Feb;41(2):297–309. doi: 10.1038/ki.1992.42. [DOI] [PubMed] [Google Scholar]
  16. Floege J., Eng E., Young B. A., Alpers C. E., Barrett T. B., Bowen-Pope D. F., Johnson R. J. Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin Invest. 1993 Dec;92(6):2952–2962. doi: 10.1172/JCI116918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Floege J., Johnson R. J., Alpers C. E., Fatemi-Nainie S., Richardson C. A., Gordon K., Couser W. G. Visceral glomerular epithelial cells can proliferate in vivo and synthesize platelet-derived growth factor B-chain. Am J Pathol. 1993 Feb;142(2):637–650. [PMC free article] [PubMed] [Google Scholar]
  18. Floege J., Johnson R. J., Gordon K., Iida H., Pritzl P., Yoshimura A., Campbell C., Alpers C. E., Couser W. G. Increased synthesis of extracellular matrix in mesangial proliferative nephritis. Kidney Int. 1991 Sep;40(3):477–488. doi: 10.1038/ki.1991.235. [DOI] [PubMed] [Google Scholar]
  19. Floege J., Topley N., Hoppe J., Barrett T. B., Resch K. Mitogenic effect of platelet-derived growth factor in human glomerular mesangial cells: modulation and/or suppression by inflammatory cytokines. Clin Exp Immunol. 1991 Nov;86(2):334–341. doi: 10.1111/j.1365-2249.1991.tb05819.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Franklin W. A., Christison W. H., Colley M., Montag A. G., Stephens J. K., Hart C. E. In situ distribution of the beta-subunit of platelet-derived growth factor receptor in nonneoplastic tissue and in soft tissue tumors. Cancer Res. 1990 Oct 1;50(19):6344–6348. [PubMed] [Google Scholar]
  21. Gesualdo L., Pinzani M., Floriano J. J., Hassan M. O., Nagy N. U., Schena F. P., Emancipator S. N., Abboud H. E. Platelet-derived growth factor expression in mesangial proliferative glomerulonephritis. Lab Invest. 1991 Aug;65(2):160–167. [PubMed] [Google Scholar]
  22. Gesualdo L., Ricanati S., Hassan M. O., Emancipator S. N., Lamm M. E. Enzymolysis of glomerular immune deposits in vivo with dextranase/protease ameliorates proteinuria, hematuria, and mesangial proliferation in murine experimental IgA nephropathy. J Clin Invest. 1990 Sep;86(3):715–722. doi: 10.1172/JCI114767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Greenhalgh D. G., Sprugel K. H., Murray M. J., Ross R. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol. 1990 Jun;136(6):1235–1246. [PMC free article] [PubMed] [Google Scholar]
  24. Gronwald R. G., Seifert R. A., Bowen-Pope D. F. Differential regulation of expression of two platelet-derived growth factor receptor subunits by transforming growth factor-beta. J Biol Chem. 1989 May 15;264(14):8120–8125. [PubMed] [Google Scholar]
  25. Hart C. E., Forstrom J. W., Kelly J. D., Seifert R. A., Smith R. A., Ross R., Murray M. J., Bowen-Pope D. F. Two classes of PDGF receptor recognize different isoforms of PDGF. Science. 1988 Jun 10;240(4858):1529–1531. doi: 10.1126/science.2836952. [DOI] [PubMed] [Google Scholar]
  26. Heldin C. H., Ostman A., Eriksson A., Siegbahn A., Claesson-Welsh L., Westermark B. Platelet-derived growth factor: isoform-specific signalling via heterodimeric or homodimeric receptor complexes. Kidney Int. 1992 Mar;41(3):571–574. doi: 10.1038/ki.1992.84. [DOI] [PubMed] [Google Scholar]
  27. Iida H., Seifert R., Alpers C. E., Gronwald R. G., Phillips P. E., Pritzl P., Gordon K., Gown A. M., Ross R., Bowen-Pope D. F. Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6560–6564. doi: 10.1073/pnas.88.15.6560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jawien A., Bowen-Pope D. F., Lindner V., Schwartz S. M., Clowes A. W. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992 Feb;89(2):507–511. doi: 10.1172/JCI115613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson R. J., Raines E. W., Floege J., Yoshimura A., Pritzl P., Alpers C., Ross R. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med. 1992 May 1;175(5):1413–1416. doi: 10.1084/jem.175.5.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Matsui T., Heidaran M., Miki T., Popescu N., La Rochelle W., Kraus M., Pierce J., Aaronson S. Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science. 1989 Feb 10;243(4892):800–804. doi: 10.1126/science.2536956. [DOI] [PubMed] [Google Scholar]
  31. Mené P., Simonson M. S., Dunn M. J. Physiology of the mesangial cell. Physiol Rev. 1989 Oct;69(4):1347–1424. doi: 10.1152/physrev.1989.69.4.1347. [DOI] [PubMed] [Google Scholar]
  32. Milani S., Herbst H., Schuppan D., Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989 Jul;10(1):84–92. doi: 10.1002/hep.1840100117. [DOI] [PubMed] [Google Scholar]
  33. Müller G. A., Markovic-Lipkovski J., Rodemann H. P. The progression of renal diseases: on the pathogenesis of renal interstitial fibrosis. Klin Wochenschr. 1991 Sep 3;69(13):576–586. doi: 10.1007/BF01649320. [DOI] [PubMed] [Google Scholar]
  34. Müller G. A., Rodemann H. P. Characterization of human renal fibroblasts in health and disease: I. Immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am J Kidney Dis. 1991 Jun;17(6):680–683. doi: 10.1016/s0272-6386(12)80351-9. [DOI] [PubMed] [Google Scholar]
  35. Palman C., Bowen-Pope D. F., Brooks J. J. Platelet-derived growth factor receptor (beta-subunit) immunoreactivity in soft tissue tumors. Lab Invest. 1992 Jan;66(1):108–115. [PubMed] [Google Scholar]
  36. Ross R. Platelet-derived growth factor. Lancet. 1989 May 27;1(8648):1179–1182. doi: 10.1016/s0140-6736(89)92760-8. [DOI] [PubMed] [Google Scholar]
  37. Ross R., Raines E. W., Bowen-Pope D. F. The biology of platelet-derived growth factor. Cell. 1986 Jul 18;46(2):155–169. doi: 10.1016/0092-8674(86)90733-6. [DOI] [PubMed] [Google Scholar]
  38. Seppä H., Grotendorst G., Seppä S., Schiffmann E., Martin G. R. Platelet-derived growth factor in chemotactic for fibroblasts. J Cell Biol. 1982 Feb;92(2):584–588. doi: 10.1083/jcb.92.2.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. Tsukamoto T., Matsui T., Nakata H., Ito M., Natazuka T., Fukase M., Fujita T. Interleukin-1 enhances the response of osteoblasts to platelet-derived growth factor through the alpha receptor-specific up-regulation. J Biol Chem. 1991 Jun 5;266(16):10143–10147. [PubMed] [Google Scholar]
  42. Yarden Y., Escobedo J. A., Kuang W. J., Yang-Feng T. L., Daniel T. O., Tremble P. M., Chen E. Y., Ando M. E., Harkins R. N., Francke U. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986 Sep 18;323(6085):226–232. doi: 10.1038/323226a0. [DOI] [PubMed] [Google Scholar]

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