Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Dec;92(6):2850–2857. doi: 10.1172/JCI116905

Expression of parathyroid hormone-related protein in the rat glomerulus and tubule during recovery from renal ischemia.

N E Soifer 1, S K Van Why 1, M B Ganz 1, M Kashgarian 1, N J Siegel 1, A F Stewart 1
PMCID: PMC288486  PMID: 8254039

Abstract

Parathyroid hormone-related protein (PTHrP) is widely expressed in normal adult and fetal tissues, where it acts in an autocrine/paracrine fashion, stimulates growth and differentiation, and shares early response gene characteristics. Since recovery from renal injury is associated with release of local growth factors, we examined the expression and localization of PTHrP in normal and ischemic adult rat kidney. Male Sprague-Dawley rats underwent complete bilateral renal artery occlusion for 45 min, followed by reperfusion for 15 min, and 2, 6, 24, 48, and 72 h. Renal PTHrP mRNA levels, when compared with sham-operated animals, increased twofold after ischemia, and peaked within 6 h after reperfusion. PTH receptor, beta-actin, and cyclophilin mRNA levels all decreased after ischemia. PTHrP immunohistochemical staining intensity increased in proximal tubular cells after ischemia, changing its location from diffusely cytoplasmic to subapical by 24 h after reperfusion. In addition, PTHrP localized to glomerular epithelial cells (visceral and parietal), but not to mesangial cells. PTHrP and PTH stimulated proliferation two- to threefold in cultured mesangial cells. We conclude that PTHrP mRNA and protein production are upregulated after acute renal ischemic injury, that PTHrP is present in glomerulus and in both proximal and distal tubular cells, and that PTHrP stimulates DNA synthesis in mesangial cells. The precise functions of PTHrP in normal and injured kidney remain to be defined.

Full text

PDF
2850

Images in this article

2852Image
on p.2852
2852Image
on p.2852
2852Image
on p.2852
2852Image
on p.2852
2852Image
on p.2852
2853Image
on p.2853
2854Image
on p.2854
2854Image
on p.2854
2854Image
on p.2854
2854Image
on p.2854
2855Image
on p.2855

Selected References

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

  1. Allinson E. T., Drucker D. J. Parathyroid hormone-like peptide shares features with members of the early response gene family: rapid induction by serum, growth factors, and cycloheximide. Cancer Res. 1992 Jun 1;52(11):3103–3109. [PubMed] [Google Scholar]
  2. 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]
  3. Barbu V., Dautry F. Northern blot normalization with a 28S rRNA oligonucleotide probe. Nucleic Acids Res. 1989 Sep 12;17(17):7115–7115. doi: 10.1093/nar/17.17.7115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burtis W. J., Brady T. G., Orloff J. J., Ersbak J. B., Warrell R. P., Jr, Olson B. R., Wu T. L., Mitnick M. E., Broadus A. E., Stewart A. F. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med. 1990 Apr 19;322(16):1106–1112. doi: 10.1056/NEJM199004193221603. [DOI] [PubMed] [Google Scholar]
  5. Burton P. B., Moniz C., Knight D. E. Parathyroid hormone related peptide can function as an autocrine growth factor in human renal cell carcinoma. Biochem Biophys Res Commun. 1990 Mar 30;167(3):1134–1138. doi: 10.1016/0006-291x(90)90641-y. [DOI] [PubMed] [Google Scholar]
  6. Burton P. B., Moniz C., Quirke P., Malik A., Bui T. D., Juppner H., Segre G. V., Knight D. E. Parathyroid hormone-related peptide: expression in fetal and neonatal development. J Pathol. 1992 Jul;167(3):291–296. doi: 10.1002/path.1711670306. [DOI] [PubMed] [Google Scholar]
  7. Campos R. V., Asa S. L., Drucker D. J. Immunocytochemical localization of parathyroid hormone-like peptide in the rat fetus. Cancer Res. 1991 Dec 1;51(23 Pt 1):6351–6357. [PubMed] [Google Scholar]
  8. Centrella M., Canalis E., McCarthy T. L., Stewart A. F., Orloff J. J., Insogna K. L. Parathyroid hormone-related protein modulates the effect of transforming growth factor-beta on deoxyribonucleic acid and collagen synthesis in fetal rat bone cells. Endocrinology. 1989 Jul;125(1):199–208. doi: 10.1210/endo-125-1-199. [DOI] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Ganz M. B., Perfetto M. C., Boron W. F. Effects of mitogens and other agents on rat mesangial cell proliferation, pH, and Ca2+. Am J Physiol. 1990 Aug;259(2 Pt 2):F269–F278. doi: 10.1152/ajprenal.1990.259.2.F269. [DOI] [PubMed] [Google Scholar]
  12. Humes H. D., Cieslinski D. A., Coimbra T. M., Messana J. M., Galvao C. Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. J Clin Invest. 1989 Dec;84(6):1757–1761. doi: 10.1172/JCI114359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Insogna K. L., Stewart A. F., Morris C. A., Hough L. M., Milstone L. M., Centrella M. Native and a synthetic analogue of the malignancy-associated parathyroid hormone-like protein have in vitro transforming growth factor-like properties. J Clin Invest. 1989 Mar;83(3):1057–1060. doi: 10.1172/JCI113947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jüppner H., Abou-Samra A. B., Freeman M., Kong X. F., Schipani E., Richards J., Kolakowski L. F., Jr, Hock J., Potts J. T., Jr, Kronenberg H. M. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024–1026. doi: 10.1126/science.1658941. [DOI] [PubMed] [Google Scholar]
  15. Kellerman P. S., Clark R. A., Hoilien C. A., Linas S. L., Molitoris B. A. Role of microfilaments in maintenance of proximal tubule structural and functional integrity. Am J Physiol. 1990 Aug;259(2 Pt 2):F279–F285. doi: 10.1152/ajprenal.1990.259.2.F279. [DOI] [PubMed] [Google Scholar]
  16. Kramer S., Reynolds F. H., Jr, Castillo M., Valenzuela D. M., Thorikay M., Sorvillo J. M. Immunological identification and distribution of parathyroid hormone-like protein polypeptides in normal and malignant tissues. Endocrinology. 1991 Apr;128(4):1927–1937. doi: 10.1210/endo-128-4-1927. [DOI] [PubMed] [Google Scholar]
  17. Lovett D. H., Sterzel R. B., Kashgarian M., Ryan J. L. Neutral proteinase activity produced in vitro by cells of the glomerular mesangium. Kidney Int. 1983 Feb;23(2):342–349. doi: 10.1038/ki.1983.25. [DOI] [PubMed] [Google Scholar]
  18. McCauley L. K., Rosol T. J., Merryman J. I., Capen C. C. Parathyroid hormone-related protein binding to human T-cell lymphotropic virus type I-infected lymphocytes. Endocrinology. 1992 Jan;130(1):300–306. doi: 10.1210/endo.130.1.1309334. [DOI] [PubMed] [Google Scholar]
  19. Molitoris B. A., Hoilien C. A., Dahl R., Ahnen D. J., Wilson P. D., Kim J. Characterization of ischemia-induced loss of epithelial polarity. J Membr Biol. 1988 Dec;106(3):233–242. doi: 10.1007/BF01872161. [DOI] [PubMed] [Google Scholar]
  20. Moniz C., Burton P. B., Malik A. N., Dixit M., Banga J. P., Nicolaides K., Quirke P., Knight D. E., McGregor A. M. Parathyroid hormone-related peptide in normal human fetal development. J Mol Endocrinol. 1990 Dec;5(3):259–266. doi: 10.1677/jme.0.0050259. [DOI] [PubMed] [Google Scholar]
  21. Pirola C. J., Wang H. M., Kamyar A., Wu S., Enomoto H., Sharifi B., Forrester J. S., Clemens T. L., Fagin J. A. Angiotensin II regulates parathyroid hormone-related protein expression in cultured rat aortic smooth muscle cells through transcriptional and post-transcriptional mechanisms. J Biol Chem. 1993 Jan 25;268(3):1987–1994. [PubMed] [Google Scholar]
  22. Rouleau M. F., Warshawsky H., Goltzman D. Parathyroid hormone binding in vivo to renal, hepatic, and skeletal tissues of the rat using a radioautographic approach. Endocrinology. 1986 Mar;118(3):919–931. doi: 10.1210/endo-118-3-919. [DOI] [PubMed] [Google Scholar]
  23. Safirstein R., Price P. M., Saggi S. J., Harris R. C. Changes in gene expression after temporary renal ischemia. Kidney Int. 1990 Jun;37(6):1515–1521. doi: 10.1038/ki.1990.143. [DOI] [PubMed] [Google Scholar]
  24. Soifer N. E., Dee K. E., Insogna K. L., Burtis W. J., Matovcik L. M., Wu T. L., Milstone L. M., Broadus A. E., Philbrick W. M., Stewart A. F. Parathyroid hormone-related protein. Evidence for secretion of a novel mid-region fragment by three different cell types. J Biol Chem. 1992 Sep 5;267(25):18236–18243. [PubMed] [Google Scholar]
  25. Sraer J., Sraer J. D., Chansel D., Jueppner H., Hesch R. D., Ardaillou R. Evidence for glomerular receptors for parathyroid hormone. Am J Physiol. 1978 Aug;235(2):F96–103. doi: 10.1152/ajprenal.1978.235.2.F96. [DOI] [PubMed] [Google Scholar]
  26. Stewart A. F., Broadus A. E. Clinical review 16: Parathyroid hormone-related proteins: coming of age in the 1990s. J Clin Endocrinol Metab. 1990 Dec;71(6):1410–1414. doi: 10.1210/jcem-71-6-1410. [DOI] [PubMed] [Google Scholar]
  27. Strewler G. J., Nissenson R. A. Hypercalcemia in malignancy. West J Med. 1990 Dec;153(6):635–640. [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Thiede M. A., Daifotis A. G., Weir E. C., Brines M. L., Burtis W. J., Ikeda K., Dreyer B. E., Garfield R. E., Broadus A. E. Intrauterine occupancy controls expression of the parathyroid hormone-related peptide gene in preterm rat myometrium. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6969–6973. doi: 10.1073/pnas.87.18.6969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Thiede M. A., Harm S. C., Hasson D. M., Gardner R. M. In vivo regulation of parathyroid hormone-related peptide messenger ribonucleic acid in the rat uterus by 17 beta-estradiol. Endocrinology. 1991 May;128(5):2317–2323. doi: 10.1210/endo-128-5-2317. [DOI] [PubMed] [Google Scholar]
  31. Toback F. G. Regeneration after acute tubular necrosis. Kidney Int. 1992 Jan;41(1):226–246. doi: 10.1038/ki.1992.32. [DOI] [PubMed] [Google Scholar]
  32. Van Why S. K., Hildebrandt F., Ardito T., Mann A. S., Siegel N. J., Kashgarian M. Induction and intracellular localization of HSP-72 after renal ischemia. Am J Physiol. 1992 Nov;263(5 Pt 2):F769–F775. doi: 10.1152/ajprenal.1992.263.5.F769. [DOI] [PubMed] [Google Scholar]
  33. de Miguel F., García-Cañero R., Esbrit P. Co-purification of calcium transport-stimulating and DNA synthesis-stimulating agents with parathormone-like activity isolated from the hypercalcaemic strain of the Walker 256 tumour. Eur J Cancer. 1991;27(8):1022–1026. doi: 10.1016/0277-5379(91)90273-g. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES