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. 1996 Jun 15;97(12):2697–2704. doi: 10.1172/JCI118723

Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome.

W E Smoyer 1, A Gupta 1, P Mundel 1, J D Ballew 1, M J Welsh 1
PMCID: PMC507361  PMID: 8675679

Abstract

Although nephrotic syndrome is a very common kidney disease, little is known about the molecular changes occurring within glomerular capillary loops during development of disease. The characteristic histologic change is retraction (effacement) of the distal "foot" processes of glomerular epithelial cells (GEC) which surround the capillary loops. The GEC foot processes are an essential part of the kidney's filtration barrier, and their structure is regulated primarily by actin microfilaments, cytoskeletal proteins present in high concentrations in foot processes. Actin polymerization has been reported to be regulated via phosphorylation of the low molecular weight heat shock protein, hsp27. We localized hsp27 within normal rat GECs using immunofluorescence and immunoelectron microscopy. Induction of nephrotic syndrome and GEC foot process effacement using the puromycin aminonucleoside rat model resulted in significant increases in: (a) renal cortical hsp27 mRNA expression (826 +/- 233%, x +/- SEM, P < 0.01 vs. control); (b) glomerular hsp27 protein expression (87 +/- 2%, P < 0.001 vs. control); and (c) glomerular hsp27 phosphorylation (101 +/- 32%, P < 0.05 vs. control). These findings support the hypothesis that hsp27, by regulating GEC foot process actin polymerization, may be important in maintaining normal foot process structure, and regulating pathophysiologic GEC cytoskeletal changes during development of nephrotic syndrome.

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Selected References

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  1. Andrews P. M., Bates S. B. Filamentous actin bundles in the kidney. Anat Rec. 1984 Sep;210(1):1–9. doi: 10.1002/ar.1092100102. [DOI] [PubMed] [Google Scholar]
  2. Bakker W. W., van Luijk W. H. Do circulating factors play a role in the pathogenesis of minimal change nephrotic syndrome? Pediatr Nephrol. 1989 Jul;3(3):341–349. doi: 10.1007/BF00858545. [DOI] [PubMed] [Google Scholar]
  3. Benndorf R., Hayess K., Ryazantsev S., Wieske M., Behlke J., Lutsch G. Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity. J Biol Chem. 1994 Aug 12;269(32):20780–20784. [PubMed] [Google Scholar]
  4. Bitar K. N., Kaminski M. S., Hailat N., Cease K. B., Strahler J. R. Hsp27 is a mediator of sustained smooth muscle contraction in response to bombesin. Biochem Biophys Res Commun. 1991 Dec 31;181(3):1192–1200. doi: 10.1016/0006-291x(91)92065-r. [DOI] [PubMed] [Google Scholar]
  5. Caulfield J. P., Reid J. J., Farquhar M. G. Alterations of the glomerular epithelium in acute aminonucleoside nephrosis. Evidence for formation of occluding junctions and epithelial cell detachment. Lab Invest. 1976 Jan;34(1):43–59. [PubMed] [Google Scholar]
  6. Ciocca D. R., Oesterreich S., Chamness G. C., McGuire W. L., Fuqua S. A. Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J Natl Cancer Inst. 1993 Oct 6;85(19):1558–1570. doi: 10.1093/jnci/85.19.1558. [DOI] [PubMed] [Google Scholar]
  7. Emami A., Schwartz J. H., Borkan S. C. Transient ischemia or heat stress induces a cytoprotectant protein in rat kidney. Am J Physiol. 1991 Apr;260(4 Pt 2):F479–F485. doi: 10.1152/ajprenal.1991.260.4.F479. [DOI] [PubMed] [Google Scholar]
  8. FARQUHAR M. G., VERNIER R. L., GOOD R. A. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus. J Exp Med. 1957 Nov 1;106(5):649–660. doi: 10.1084/jem.106.5.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Freshney N. W., Rawlinson L., Guesdon F., Jones E., Cowley S., Hsuan J., Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039–1049. doi: 10.1016/0092-8674(94)90278-x. [DOI] [PubMed] [Google Scholar]
  10. Hoyer J. R., Ratte J., Potter A. H., Michael A. F. Transfer of aminonucleoside nephrosis by renal transplantation. J Clin Invest. 1972 Oct;51(10):2777–2780. doi: 10.1172/JCI107099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Huot J., Houle F., Spitz D. R., Landry J. HSP27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res. 1996 Jan 15;56(2):273–279. [PubMed] [Google Scholar]
  12. Huot J., Roy G., Lambert H., Chrétien P., Landry J. Increased survival after treatments with anticancer agents of Chinese hamster cells expressing the human Mr 27,000 heat shock protein. Cancer Res. 1991 Oct 1;51(19):5245–5252. [PubMed] [Google Scholar]
  13. Ito K., Ger Y. C., Kawamura S. Actin filament alterations in glomerular epithelial cells of adriamycin-induced nephrotic rats. Acta Pathol Jpn. 1986 Feb;36(2):253–260. doi: 10.1111/j.1440-1827.1986.tb01477.x. [DOI] [PubMed] [Google Scholar]
  14. Jakob U., Gaestel M., Engel K., Buchner J. Small heat shock proteins are molecular chaperones. J Biol Chem. 1993 Jan 25;268(3):1517–1520. [PubMed] [Google Scholar]
  15. Klein D. J., Dehnel P. J., Oegema T. R., Brown D. M. Alterations in proteoglycan metabolism in the nephrotic syndrome induced by the aminonucleoside of puromycin. Lab Invest. 1984 May;50(5):543–551. [PubMed] [Google Scholar]
  16. Komatsuda A., Wakui H., Imai H., Nakamoto Y., Miura A. B., Itoh H., Tashima Y. Renal localization of the constitutive 73-kDa heat-shock protein in normal and PAN rats. Kidney Int. 1992 May;41(5):1204–1212. doi: 10.1038/ki.1992.182. [DOI] [PubMed] [Google Scholar]
  17. Koyama A., Fujisaki M., Kobayashi M., Igarashi M., Narita M. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int. 1991 Sep;40(3):453–460. doi: 10.1038/ki.1991.232. [DOI] [PubMed] [Google Scholar]
  18. Kreisberg J. I., Hoover R. L., Karnovsky M. J. Isolation and characterization of rat glomerular epithelial cells in vitro. Kidney Int. 1978 Jul;14(1):21–30. doi: 10.1038/ki.1978.86. [DOI] [PubMed] [Google Scholar]
  19. Lachapelle M., Bendayan M. Contractile proteins in podocytes: immunocytochemical localization of actin and alpha-actinin in normal and nephrotic rat kidneys. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(2):105–111. doi: 10.1007/BF02899534. [DOI] [PubMed] [Google Scholar]
  20. Lagrue G., Laurent J., Rostoker G. Food allergy and idiopathic nephrotic syndrome. Kidney Int Suppl. 1989 Nov;27:S147–S151. [PubMed] [Google Scholar]
  21. Landry J., Chrétien P., Lambert H., Hickey E., Weber L. A. Heat shock resistance conferred by expression of the human HSP27 gene in rodent cells. J Cell Biol. 1989 Jul;109(1):7–15. doi: 10.1083/jcb.109.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lavoie J. N., Gingras-Breton G., Tanguay R. M., Landry J. Induction of Chinese hamster HSP27 gene expression in mouse cells confers resistance to heat shock. HSP27 stabilization of the microfilament organization. J Biol Chem. 1993 Feb 15;268(5):3420–3429. [PubMed] [Google Scholar]
  23. Lavoie J. N., Hickey E., Weber L. A., Landry J. Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem. 1993 Nov 15;268(32):24210–24214. [PubMed] [Google Scholar]
  24. Lavoie J. N., Lambert H., Hickey E., Weber L. A., Landry J. Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27. Mol Cell Biol. 1995 Jan;15(1):505–516. doi: 10.1128/mcb.15.1.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Levin M., Gascoine P., Turner M. W., Barratt T. M. A highly cationic protein in plasma and urine of children with steroid-responsive nephrotic syndrome. Kidney Int. 1989 Nov;36(5):867–877. doi: 10.1038/ki.1989.273. [DOI] [PubMed] [Google Scholar]
  26. Lindquist S., Craig E. A. The heat-shock proteins. Annu Rev Genet. 1988;22:631–677. doi: 10.1146/annurev.ge.22.120188.003215. [DOI] [PubMed] [Google Scholar]
  27. Matsubara O., Kasuga T., Marumo F., Itoh H., Tashima Y. Localization of 90-kDa heat shock protein in the kidney. Kidney Int. 1990 Nov;38(5):830–834. doi: 10.1038/ki.1990.278. [DOI] [PubMed] [Google Scholar]
  28. Mehlen P., Briolay J., Smith L., Diaz-latoud C., Fabre N., Pauli D., Arrigo A. P. Analysis of the resistance to heat and hydrogen peroxide stresses in COS cells transiently expressing wild type or deletion mutants of the Drosophila 27-kDa heat-shock protein. Eur J Biochem. 1993 Jul 15;215(2):277–284. doi: 10.1111/j.1432-1033.1993.tb18032.x. [DOI] [PubMed] [Google Scholar]
  29. Mehlen P., Preville X., Chareyron P., Briolay J., Klemenz R., Arrigo A. P. Constitutive expression of human hsp27, Drosophila hsp27, or human alpha B-crystallin confers resistance to TNF- and oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts. J Immunol. 1995 Jan 1;154(1):363–374. [PubMed] [Google Scholar]
  30. Miron T., Vancompernolle K., Vandekerckhove J., Wilchek M., Geiger B. A 25-kD inhibitor of actin polymerization is a low molecular mass heat shock protein. J Cell Biol. 1991 Jul;114(2):255–261. doi: 10.1083/jcb.114.2.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Miron T., Wilchek M., Geiger B. Characterization of an inhibitor of actin polymerization in vinculin-rich fraction of turkey gizzard smooth muscle. Eur J Biochem. 1988 Dec 15;178(2):543–553. doi: 10.1111/j.1432-1033.1988.tb14481.x. [DOI] [PubMed] [Google Scholar]
  32. Moorthy A. V., Zimmerman S. W., Burkholder P. M. Inhibition of lymphocyte blastogenesis by plasma of patients with minimal-change nephrotic syndrome. Lancet. 1976 May 29;1(7970):1160–1162. doi: 10.1016/s0140-6736(76)91545-2. [DOI] [PubMed] [Google Scholar]
  33. Nakamura T., Ebihara I., Shirato I., Tomino Y., Koide H. Modulation of basement membrane component gene expression in glomeruli of aminonucleoside nephrosis. Lab Invest. 1991 May;64(5):640–647. [PubMed] [Google Scholar]
  34. Rollet E., Lavoie J. N., Landry J., Tanguay R. M. Expression of Drosophila's 27 kDa heat shock protein into rodent cells confers thermal resistance. Biochem Biophys Res Commun. 1992 May 29;185(1):116–120. doi: 10.1016/s0006-291x(05)80963-5. [DOI] [PubMed] [Google Scholar]
  35. Ross W. R., Bertrand W. S., Morrison A. R. Identification of a processed protein related to the human chaperonins (hsp 60) protein in mammalian kidney. Biochem Biophys Res Commun. 1992 Jun 15;185(2):683–687. doi: 10.1016/0006-291x(92)91679-k. [DOI] [PubMed] [Google Scholar]
  36. Rothman J. E. Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell. 1989 Nov 17;59(4):591–601. doi: 10.1016/0092-8674(89)90005-6. [DOI] [PubMed] [Google Scholar]
  37. Ryan G. B., Karnovsky M. J. An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis. Kidney Int. 1975 Oct;8(4):219–232. doi: 10.1038/ki.1975.105. [DOI] [PubMed] [Google Scholar]
  38. Schnaper H. W., Aune T. M. Identification of the lymphokine soluble immune response suppressor in urine of nephrotic children. J Clin Invest. 1985 Jul;76(1):341–349. doi: 10.1172/JCI111967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schnaper H. W., Aune T. M. Steroid-sensitive mechanism of soluble immune response suppressor production in steroid-responsive nephrotic syndrome. J Clin Invest. 1987 Jan;79(1):257–264. doi: 10.1172/JCI112792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sharma R., Lovell H. B., Wiegmann T. B., Savin V. J. Vasoactive substances induce cytoskeletal changes in cultured rat glomerular epithelial cells. J Am Soc Nephrol. 1992 Nov;3(5):1131–1138. doi: 10.1681/ASN.V351131. [DOI] [PubMed] [Google Scholar]
  41. Sobel A. T., Branellec A. I., Blanc C. J., Lagrue G. A. Physicochemical characterization of a vascular permeability factor produced by con A-stimulated human lymphocytes. J Immunol. 1977 Oct;119(4):1230–1234. [PubMed] [Google Scholar]
  42. VERNIER R. L., PAPERMASTER B. W., GOOD R. A. Aminonucleoside nephrosis. I. Electron microscopic study of the renal lesion in rats. J Exp Med. 1959 Jan 1;109(1):115–126. doi: 10.1084/jem.109.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vasmant D., Maurice M., Feldmann G. Cytoskeleton ultrastructure of podocytes and glomerular endothelial cells in man and in the rat. Anat Rec. 1984 Sep;210(1):17–24. doi: 10.1002/ar.1092100104. [DOI] [PubMed] [Google Scholar]
  44. Wakui H., Itoh H., Tashima Y., Kobayashi R., Nakamoto Y., Miura A. B. Purification of a mature form of 60 kDa heat-shock protein (chaperonin homolog) from porcine kidney and its partial amino acid sequence. Int J Biochem. 1992 Sep;24(9):1507–1510. doi: 10.1016/0020-711x(92)90079-g. [DOI] [PubMed] [Google Scholar]
  45. Welch W. J. Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol Rev. 1992 Oct;72(4):1063–1081. doi: 10.1152/physrev.1992.72.4.1063. [DOI] [PubMed] [Google Scholar]
  46. Whiteside C. I., Cameron R., Munk S., Levy J. Podocytic cytoskeletal disaggregation and basement-membrane detachment in puromycin aminonucleoside nephrosis. Am J Pathol. 1993 May;142(5):1641–1653. [PMC free article] [PubMed] [Google Scholar]
  47. Whiteside C., Prutis K., Cameron R., Thompson J. Glomerular epithelial detachment, not reduced charge density, correlates with proteinuria in adriamycin and puromycin nephrosis. Lab Invest. 1989 Dec;61(6):650–660. [PubMed] [Google Scholar]

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