Skip to main content

Advertisement

SpringerLink
Log in

Dissociation of renal cyclic AMP and phosphate responses to parathyroid hormone in uremia

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Summary

Various investigators have shown that chronic uremia is associated with a normal or exaggerated phosphaturic response to parathyroid hormone (PTH). To explore the relationship between progressive uremia, renal tubular cyclic AMP (cAMP), and inorganic phosphate (Pi) response to PTH and acidosis, in vivo and in vitro experiments were designed in rats with experimental uremia of 4–6 weeks’ duration. Both uremic and pair-fed control rats were treated with 1,25-dihydroxycholecalciferol (1,25(OH)2D3) and/or chronic NH4Cl feeding. Urinary Pi and cAMP and plasma immunoreactive PTH (iPTH) were measured as well as PTH- and NaF-stimulated cAMP from isolated renal tubules. Excretion of cAMP decreased by 30% in uremic as compared to control rats despite a 3-fold rise in Pi excretion. Acidosis superimposed on uremia did not further decrease cAMP excretion, nor did it significantly alter the elevated Pi excretion. 1,25(OH)2D3 treatment of uremic rats further lowered cAMP excretion although Pi excretion rose, hypercalcemia occurred, and plasma iPTH fell. In nonuremic control rats, 1,25(OH)2D3 treatment led to hypercalcemia, a progressive decrease in cAMP, and increase in Pi excretion. Isolated renal tubules from uremic or acidotic uremic rats revealed a 50% reduction in both PTH- and NaF-stimulated cAMP generation compared to control rat renal tubules. This observation was unchanged by 1,25(OH)2D3 treatment. Renal tubules of 1,25(OH)2D3-treated control rats demonstrated a decreased cAMP production in response to both PTH and NaF which was inversely related to the calcium content of the renal tubules. Renal tubular calcium levels of uremic rats, initially 3-fold elevated, also increased during 1,25(OH)2D3 treatment. These results are consistent with the hypothesis that progressive uremia results in a dissociation between PTH, urinary cAMP, and Pi excretion which cannot be explained by either metabolic acidosis or 1,25(OH)2D3 deficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Slatopolsky, E., Caglar, S., Pennell, J.P., Taggert, D.P., Canterbury, J.L., Reiss, E., Bricker, N.S.: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog, J. Clin, Invest.50:492–499, 1971

    CAS  Google Scholar 

  2. Bricker, N.S.: On the pathogenesis of the uremic state. An exposition of the “trade-off” hypothesis, N. Engl. J. Med.286:1093–1099, 1972

    Article  PubMed  CAS  Google Scholar 

  3. Nagata, N., Rasmussen, H.: Parathyroid hormone and renal cell metabolism, Biochemistry7:3728–3733, 1968

    Article  PubMed  CAS  Google Scholar 

  4. Agus, Z.S., Puschett, J.B., Senesky, D., Goldberg, M.: Mode of action of parathyroid hormone and cyclic adenosine 3′,5′-monophosphate on renal tubular phosphate reabsorption in the dog, J. Clin. Invest.50:617–626, 1971

    PubMed  CAS  Google Scholar 

  5. Chase, L.R., Aurbach, G.D.: Parathyroid function and the renal excretion of 3′,5′-adenylic acid, Proc. Natl. Acad. Sci. U.S.A.58:518–525, 1967

    PubMed  CAS  Google Scholar 

  6. Purkerson, M.L., Rolf, D., Miller, S., Slatopolsky, E., Klahr, S.: Evidence for increased nephron sensitivity to parathyroid hormone (PTH) is renal mass is decreased, Clin. Res.24:591A, 1976 (abstr.)

  7. Beck, N., Kim, H.P., Kim, K.S.: Effect of metabolic acidosis on renal action of parathyroid hormone, Am. J. Physiol.228:1483–1488, 1975

    PubMed  CAS  Google Scholar 

  8. Russell, J.E., Avioli, L.V.: Effect of experimental chronic renal insufficiency on bone mineral and collagen maturation, J. Clin. Invest.51:3072, 3079, 1972

    PubMed  CAS  Google Scholar 

  9. Brumbaugh, P.F., Haussler, D.H., Bressler, R., Haussler, M.R.: Radioreceptor assay 1α, 25-dihydroxyvitamin D3, Science183:1089–1091, 1974.

    PubMed  CAS  Google Scholar 

  10. Forte, L.R., Nickols, G.A., Anast, C.S.: Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3′,5′-monophosphate excretion, J. Clin. Invest.57:559–568, 1976

    PubMed  CAS  Google Scholar 

  11. Chanard, J., Block, R., Purkerson, M., Lewis, J., Klahr, S., Slatopolsky, E.: The effects of colchicine and vinblastine on parathyroid hormone secretion in the rat, Endocrinology101:1792–1800, 1977

    PubMed  CAS  Google Scholar 

  12. Shain, S.A.: Thein vitro metabolism of 25-hydroxy-cholecalciferol to 1,25-dihydroxycholecalciferol by chick renal tubules, J. Biol. Chem.247:4404–4413, 1972

    PubMed  CAS  Google Scholar 

  13. Peytremann, A., Goltzman, D., Callahan, E.N., Tregear, G.W., Potts, J.T., Jr.: Metabolism and biologic activity of proparathyroid hormone and synthetic analogues in renal cortical membranes, Endocrinology97:1270–1280, 1975

    PubMed  CAS  Google Scholar 

  14. Di Belle, F.P., Arnaud, C.D., Brewer, H.B., Jr.: relative biologic activities of human and bovine parathyroid hormones and their synthetic, NH2-terminal (1–34) peptides, as evaluatedin vitro with renal cortical adenylate cyclase obtained from three different species, Endocrinology99:429–436, 1976

    Google Scholar 

  15. Lowry, O.H., Rosenbrough, N.J., Farr, A.L., Randall, R.J.: Protein measurement by the Folin phenol reagent, J. Biol. Chem.193:256–275, 1951

    Google Scholar 

  16. Kepner, B.L., Hercules, D.M.: Fluorometric determination of calcium in blood serum, Anal. Chem.35:1238–1243, 1963

    Article  CAS  Google Scholar 

  17. Barzel, U.S., Jowsey, J.: The effects of chronic acid and alkali administration on bone turnover in adult rats, Clin. Sci.36:517–524, 1969

    PubMed  CAS  Google Scholar 

  18. Beck, N., Singh, H., Reed, S.W., Davis, B.B.: Direct inhibitory effect of hypercalcemia on renal actions of parathyroid hormone, J. Clin. Invest.53:717–725, 1974

    PubMed  CAS  Google Scholar 

  19. Aurbach, G.D., Chase, L.R.: Cyclic 3′,5′-adenylic acid in bone and the mechanisms of action of parathyroid hormone, Fed. Proc.29:1179–1182, 1970

    PubMed  CAS  Google Scholar 

  20. Peck, W.A., Carpenter, J., Messinger, K., DeBra, D.: Cyclic 3′,5′-adenosine monophosphate in isolated bone cells: response to low concentrations of parathyroid hormone, Endocrinology92:692–697, 1973

    Article  PubMed  CAS  Google Scholar 

  21. Smith, D.M., Johnston, C., Jr.: Hormonal responsiveness of adenylate cyclase activity from separated bone cells, Endocrinology95:130–139, 1974

    PubMed  CAS  Google Scholar 

  22. Slatopolsky, E., Mercado, A., Morrison, A., Yates, J., Klahr, S.: Inhibitory effects of hypermagnesemia on the renal action of parathyroid hormone, J. Clin. Invest.58:1273–1279, 1976

    PubMed  CAS  Google Scholar 

  23. Beck, N., Webster, S.K.: Effects of acute metabolic acidosis on parathyroid hormone action and calcium mobilization, Am. J. Physiol.230:(1): 127–131, 1976

    PubMed  CAS  Google Scholar 

  24. Mautalen, C., Montoreano, R., Labarrere, C.: Early skeletal effect of alkali therapy upon the osteomalacia of renal tubular acidosis, J. Clin. Endocrinol. Metab.42:875–881, 1976

    Article  PubMed  CAS  Google Scholar 

  25. Chertow, B.S., Baylink, D.J., Wergedal, J.E., Su, M.H.H., Norman, A.W.: Decrease in serum immunoreactive parathyroid hormone in rats and in parathyroid hormone secretionin vitro by 1,25-dihydroxycholecalciferol, J. Clin. Invest.56:668–678, 1975

    Article  PubMed  CAS  Google Scholar 

  26. Henry, H.L., Taylor, A.N., Norman, A.W.: Response of chick parathyroid glands to the vitamin D metabolites 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol, N. Nutr.107:1918–1926, 1977

    CAS  Google Scholar 

  27. Chertow, B.S., Baker, G.R., Henry, H.L., Norman, A.W.: Inhibition of parathyroid hormone secretion by vitamin D metabolites, Clin. Res.26:412A, 1978 (abstr.)

  28. Canterbury, J.M., Lerman, S., Claflin, A.J., Henry, H., Norman, A., Reiss, E.: Inhibition of parathyroid hormone secretion by 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol in the dog, J. Clin. Invest.61:1375–1383, 1978

    PubMed  CAS  Google Scholar 

  29. Oldham, S.B., Smith, R., Hartenbower, D.L., Henry, H.L.: Effects of 1,25-dihydroxycholecalciferol on serum calcium, phosphate and immunoreactive parathyroid hormone in dogs, Adv. Exp. Med. Biol.103: (in press)

  30. Golden, P., Mazey, R., Greenwalt, A., Martin, K., Slatopolsky, E.: Vitamin D: a direct effect on the parathyroid gland? Mineral Electrolyte Metab. (in press)

  31. Scarpelli, D.G., Tremblay, G., Pearse, A.G.E.: A comparative cytochemical and cytologic study of vitamin D induced nephrocalcinosis, Am. J. Pathol.36:331–353, 1960

    PubMed  CAS  Google Scholar 

  32. Ibels, L.S., Alfrey, A.C., Haut, L., Huffer, W.E.: Preservation of function in experimental renal disease by dietary restriction of phosphate, N. Engl. J. Med.298:122–126, 1978

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. J. E. Russell

    Present address: Department of Medicine, Division of Bone and Mineral Metabolism and Division of Nephrology, Washington University, School of Medicine, 63110, St. Louis, Missouri, USA

Authors and Affiliations

  1. Department of Medicine, Division of Bone and Mineral Metabolism and Division of Nephrology, Washington University, School of Medicine, 63110, St. Louis, Missouri, USA

    M. Kleerekoper, E. Slatopolsky, J. Lewis, S. W. Lee & L. V. Avioli M.D.

Authors
  1. J. E. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Kleerekoper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Slatopolsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. W. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. V. Avioli M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russell, J.E., Kleerekoper, M., Slatopolsky, E. et al. Dissociation of renal cyclic AMP and phosphate responses to parathyroid hormone in uremia. Calcif Tissue Int 29, 147–154 (1979). https://doi.org/10.1007/BF02408070

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02408070

Key words

Search

Navigation