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. 1997 Mar 15;99(6):1217–1223. doi: 10.1172/JCI119278

Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins.

J A Tumlin 1, J P Lea 1, C E Swanson 1, C L Smith 1, S S Edge 1, J S Someren 1
PMCID: PMC507935  PMID: 9077529

Abstract

Heat shock proteins (HSP) are components of the steroid receptor complex and are released into the cell cytosol after hormone binding. We tested whether HSPs released from steroid receptors mediate an increase in calcineurin phosphatase activity by steroid hormones. Aldosterone increased calcineurin activity in microdissected rat cortical collecting ducts (CCD) and connecting tubules, but not in proximal tubules, medullary thick ascending limb, or outer medullary collecting ducts. In contrast, 5 microM dexamethasone increased calcineurin activity in both CCD and proximal tubules. Aldosterone increased CCD calcineurin activity after 30 min and this response was blocked by spironolactone, but not by actinomycin D. An antibody recognizing HSP-56 did not change basal calcineurin activity, but completely blocked the stimulation of calcineurin by aldosterone. Rapamycin, an immunosuppressive drug that stabilizes the HSP-steroid receptor complex, also blocked the aldosterone response, whereas HSP-90 or HSP-70 increased calcineurin activity in permeabilized CCD. In summary, (a) aldosterone increases calcineurin activity in CCD through a transcription-independent process; (b) maneuvers inactivating HSP-56 or slowing HSP disassociation from the receptor complex blocks stimulation of calcineurin by steroid hormones; (c) HSP-90 and HSP-70 increase CCD calcineurin activity in the absence of steroid hormone. We conclude that HSPs released from transformed steroid receptors can stimulate calcineurin activity through a transcription-independent pathway.

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Selected References

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  1. Aperia A., Ibarra F., Svensson L. B., Klee C., Greengard P. Calcineurin mediates alpha-adrenergic stimulation of Na+,K(+)-ATPase activity in renal tubule cells. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7394–7397. doi: 10.1073/pnas.89.16.7394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chang J. Y., Sehgal S. N., Bansbach C. C. FK506 and rapamycin: novel pharmacological probes of the immune response. Trends Pharmacol Sci. 1991 Jun;12(6):218–223. doi: 10.1016/0165-6147(91)90555-7. [DOI] [PubMed] [Google Scholar]
  3. Christ M., Douwes K., Eisen C., Bechtner G., Theisen K., Wehling M. Rapid effects of aldosterone on sodium transport in vascular smooth muscle cells. Hypertension. 1995 Jan;25(1):117–123. doi: 10.1161/01.hyp.25.1.117. [DOI] [PubMed] [Google Scholar]
  4. Dumont F. J., Staruch M. J., Koprak S. L., Siekierka J. J., Lin C. S., Harrison R., Sewell T., Kindt V. M., Beattie T. R., Wyvratt M. The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin. J Exp Med. 1992 Sep 1;176(3):751–760. doi: 10.1084/jem.176.3.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fujii Y., Takemoto F., Katz A. I. Early effects of aldosterone on Na-K pump in rat cortical collecting tubules. Am J Physiol. 1990 Jul;259(1 Pt 2):F40–F45. doi: 10.1152/ajprenal.1990.259.1.F40. [DOI] [PubMed] [Google Scholar]
  6. Kost S. L., Smith D. F., Sullivan W. P., Welch W. J., Toft D. O. Binding of heat shock proteins to the avian progesterone receptor. Mol Cell Biol. 1989 Sep;9(9):3829–3838. doi: 10.1128/mcb.9.9.3829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Lea J. P., Sands J. M., McMahon S. J., Tumlin J. A. Evidence that the inhibition of Na+/K(+)-ATPase activity by FK506 involves calcineurin. Kidney Int. 1994 Sep;46(3):647–652. doi: 10.1038/ki.1994.317. [DOI] [PubMed] [Google Scholar]
  8. Lebeau M. C., Massol N., Herrick J., Faber L. E., Renoir J. M., Radanyi C., Baulieu E. E. P59, an hsp 90-binding protein. Cloning and sequencing of its cDNA and preparation of a peptide-directed polyclonal antibody. J Biol Chem. 1992 Mar 5;267(7):4281–4284. [PubMed] [Google Scholar]
  9. Liu A. Y., Greengard P. Aldosterone-induced increase in protein phosphatase activity of toad bladder. Proc Natl Acad Sci U S A. 1974 Oct;71(10):3869–3873. doi: 10.1073/pnas.71.10.3869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mivechi N. F., Trainor L. D., Hahn G. M. Purified mammalian HSP-70 KDA activates phosphoprotein phosphatases in vitro. Biochem Biophys Res Commun. 1993 Apr 30;192(2):954–963. doi: 10.1006/bbrc.1993.1508. [DOI] [PubMed] [Google Scholar]
  11. Miyata Y., Yahara I. Cytoplasmic 8 S glucocorticoid receptor binds to actin filaments through the 90-kDa heat shock protein moiety. J Biol Chem. 1991 May 15;266(14):8779–8783. [PubMed] [Google Scholar]
  12. Ning Y. M., Sánchez E. R. Evidence for a functional interaction between calmodulin and the glucocorticoid receptor. Biochem Biophys Res Commun. 1995 Mar 8;208(1):48–54. doi: 10.1006/bbrc.1995.1303. [DOI] [PubMed] [Google Scholar]
  13. Ning Y. M., Sánchez E. R. Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin. J Biol Chem. 1993 Mar 25;268(9):6073–6076. [PubMed] [Google Scholar]
  14. Palmer L. G., Antonian L., Frindt G. Regulation of the Na-K pump of the rat cortical collecting tubule by aldosterone. J Gen Physiol. 1993 Jul;102(1):43–57. doi: 10.1085/jgp.102.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Palmer L. G., Speez N. Stimulation of apical Na permeability and basolateral Na pump of toad urinary bladder by aldosterone. Am J Physiol. 1986 Feb;250(2 Pt 2):F273–F281. doi: 10.1152/ajprenal.1986.250.2.F273. [DOI] [PubMed] [Google Scholar]
  16. Pratt W. B. The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor. J Biol Chem. 1993 Oct 15;268(29):21455–21458. [PubMed] [Google Scholar]
  17. Pratt W. B. Transformation of glucocorticoid and progesterone receptors to the DNA-binding state. J Cell Biochem. 1987 Sep;35(1):51–68. doi: 10.1002/jcb.240350105. [DOI] [PubMed] [Google Scholar]
  18. Renoir J. M., Le Bihan S., Mercier-Bodard C., Gold A., Arjomandi M., Radanyi C., Baulieu E. E. Effects of immunosuppressants FK506 and rapamycin on the heterooligomeric form of the progesterone receptor. J Steroid Biochem Mol Biol. 1994 Jan;48(1):101–110. doi: 10.1016/0960-0760(94)90256-9. [DOI] [PubMed] [Google Scholar]
  19. Sands J. M., Terada Y., Bernard L. M., Knepper M. A. Aldose reductase activities in microdissected rat renal tubule segments. Am J Physiol. 1989 Apr;256(4 Pt 2):F563–F569. doi: 10.1152/ajprenal.1989.256.4.F563. [DOI] [PubMed] [Google Scholar]
  20. Tai P. K., Albers M. W., Chang H., Faber L. E., Schreiber S. L. Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex. Science. 1992 May 29;256(5061):1315–1318. doi: 10.1126/science.1376003. [DOI] [PubMed] [Google Scholar]
  21. Takai A., Mieskes G. Inhibitory effect of okadaic acid on the p-nitrophenyl phosphate phosphatase activity of protein phosphatases. Biochem J. 1991 Apr 1;275(Pt 1):233–239. doi: 10.1042/bj2750233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tumlin J. A., Hoban C. A., Medford R. M., Sands J. M. Expression of Na-K-ATPase alpha- and beta-subunit mRNA and protein isoforms in the rat nephron. Am J Physiol. 1994 Feb;266(2 Pt 2):F240–F245. doi: 10.1152/ajprenal.1994.266.2.F240. [DOI] [PubMed] [Google Scholar]
  24. Tumlin J. A., Sands J. M. Nephron segment-specific inhibition of Na+/K(+)-ATPase activity by cyclosporin A. Kidney Int. 1993 Jan;43(1):246–251. doi: 10.1038/ki.1993.38. [DOI] [PubMed] [Google Scholar]
  25. Tumlin J. A., Someren J. T., Swanson C. E., Lea J. P. Expression of calcineurin activity and alpha-subunit isoforms in specific segments of the rat nephron. Am J Physiol. 1995 Oct;269(4 Pt 2):F558–F563. doi: 10.1152/ajprenal.1995.269.4.F558. [DOI] [PubMed] [Google Scholar]
  26. Ueki K., Muramatsu T., Kincaid R. L. Structure and expression of two isoforms of the murine calmodulin-dependent protein phosphatase regulatory subunit (calcineurin B). Biochem Biophys Res Commun. 1992 Aug 31;187(1):537–543. doi: 10.1016/s0006-291x(05)81527-x. [DOI] [PubMed] [Google Scholar]
  27. Verrey F., Schaerer E., Zoerkler P., Paccolat M. P., Geering K., Kraehenbuhl J. P., Rossier B. C. Regulation by aldosterone of Na+,K+-ATPase mRNAs, protein synthesis, and sodium transport in cultured kidney cells. J Cell Biol. 1987 May;104(5):1231–1237. doi: 10.1083/jcb.104.5.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wehling M., Neylon C. B., Fullerton M., Bobik A., Funder J. W. Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells. Circ Res. 1995 Jun;76(6):973–979. doi: 10.1161/01.res.76.6.973. [DOI] [PubMed] [Google Scholar]

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