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. 1992 May;89(5):1485–1495. doi: 10.1172/JCI115739

Parathyroid hormone decreases HCO3 reabsorption in the rat proximal tubule by stimulating phosphatidylinositol metabolism and inhibiting base exit.

E Pastoriza-Munoz 1, R M Harrington 1, M L Graber 1
PMCID: PMC443019  PMID: 1314850

Abstract

The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pHi) was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PTH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal HCO3 reabsorption.

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Selected References

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  1. 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. 1971 Mar;50(3):617–626. doi: 10.1172/JCI106532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alpern R. J., Chambers M. Cell pH in the rat proximal convoluted tubule. Regulation by luminal and peritubular pH and sodium concentration. J Clin Invest. 1986 Aug;78(2):502–510. doi: 10.1172/JCI112602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alpern R. J. Mechanism of basolateral membrane H+/OH-/HCO-3 transport in the rat proximal convoluted tubule. A sodium-coupled electrogenic process. J Gen Physiol. 1985 Nov;86(5):613–636. doi: 10.1085/jgp.86.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aronson P. S., Nee J., Suhm M. A. Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature. 1982 Sep 9;299(5879):161–163. doi: 10.1038/299161a0. [DOI] [PubMed] [Google Scholar]
  5. Baum M., Hays S. R. Phorbol myristate acetate and dioctanoylglycerol inhibit transport in rabbit proximal convoluted tubule. Am J Physiol. 1988 Jan;254(1 Pt 2):F9–14. doi: 10.1152/ajprenal.1988.254.1.F9. [DOI] [PubMed] [Google Scholar]
  6. Boron W. F., Sackin H. Measurement of intracellular ionic composition and activities in renal tubules. Annu Rev Physiol. 1983;45:483–496. doi: 10.1146/annurev.ph.45.030183.002411. [DOI] [PubMed] [Google Scholar]
  7. DuBose T. D., Jr, Pucacco L. R., Lucci M. S., Carter N. W. Micropuncture determination of pH, PCO2, and total CO2 concentration in accessible structures of the rat renal cortex. J Clin Invest. 1979 Aug;64(2):476–482. doi: 10.1172/JCI109485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Goligorsky M. S., Loftus D. J., Hruska K. A. Cytoplasmic calcium in individual proximal tubular cells in culture. Am J Physiol. 1986 Nov;251(5 Pt 2):F938–F944. doi: 10.1152/ajprenal.1986.251.5.F938. [DOI] [PubMed] [Google Scholar]
  9. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  10. Hammerman M. R., Rogers S., Morrissey J. J., Gavin J. R., 3rd Phorbol ester-stimulated phosphorylation of basolateral membranes from canine kidney. Am J Physiol. 1986 Jun;250(6 Pt 2):F1073–F1081. doi: 10.1152/ajprenal.1986.250.6.F1073. [DOI] [PubMed] [Google Scholar]
  11. Hassid A., Pidikiti N., Gamero D. Effects of vasoactive peptides on cytosolic calcium in cultured mesangial cells. Am J Physiol. 1986 Dec;251(6 Pt 2):F1018–F1028. doi: 10.1152/ajprenal.1986.251.6.F1018. [DOI] [PubMed] [Google Scholar]
  12. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  13. Hruska K. A., Goligorsky M., Scoble J., Tsutsumi M., Westbrook S., Moskowitz D. Effects of parathyroid hormone on cytosolic calcium in renal proximal tubular primary cultures. Am J Physiol. 1986 Aug;251(2 Pt 2):F188–F198. doi: 10.1152/ajprenal.1986.251.2.F188. [DOI] [PubMed] [Google Scholar]
  14. Hruska K. A., Moskowitz D., Esbrit P., Civitelli R., Westbrook S., Huskey M. Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone. J Clin Invest. 1987 Jan;79(1):230–239. doi: 10.1172/JCI112788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kahn A. M., Dolson G. M., Hise M. K., Bennett S. C., Weinman E. J. Parathyroid hormone and dibutyryl cAMP inhibit Na+/H+ exchange in renal brush border vesicles. Am J Physiol. 1985 Feb;248(2 Pt 2):F212–F218. doi: 10.1152/ajprenal.1985.248.2.F212. [DOI] [PubMed] [Google Scholar]
  16. Khalifa S., Mills S., Hruska K. A. Stimulation of calcium uptake by parathyroid hormone in renal brush-border membrane vesicles. Relationship to membrane phosphorylation. J Biol Chem. 1983 Dec 10;258(23):14400–14406. [PubMed] [Google Scholar]
  17. Kinsella J. L., Aronson P. S. Properties of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol. 1980 Jun;238(6):F461–F469. doi: 10.1152/ajprenal.1980.238.6.F461. [DOI] [PubMed] [Google Scholar]
  18. Krapf R., Alpern R. J., Rector F. C., Jr, Berry C. A. Basolateral membrane Na/base cotransport is dependent on CO2/HCO3 in the proximal convoluted tubule. J Gen Physiol. 1987 Dec;90(6):833–853. doi: 10.1085/jgp.90.6.833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Liu F. Y., Cogan M. G. Role of protein kinase C in proximal bicarbonate absorption and angiotensin signaling. Am J Physiol. 1990 Apr;258(4 Pt 2):F927–F933. doi: 10.1152/ajprenal.1990.258.4.F927. [DOI] [PubMed] [Google Scholar]
  20. McKinney T. D., Myers P. Bicarbonate transport by proximal tubules: effect of parathyroid hormone and dibutyryl cyclic AMP. Am J Physiol. 1980 Mar;238(3):F166–F174. doi: 10.1152/ajprenal.1980.238.3.F166. [DOI] [PubMed] [Google Scholar]
  21. Mellas J., Hammerman M. R. Phorbol ester-induced alkalinization of canine renal proximal tubular cells. Am J Physiol. 1986 Mar;250(3 Pt 2):F451–F459. doi: 10.1152/ajprenal.1986.250.3.F451. [DOI] [PubMed] [Google Scholar]
  22. Pastoriza-Munoz E., Harrington R. M., Graber M. L. Axial heterogeneity of intracellular pH in rat proximal convoluted tubule. J Clin Invest. 1987 Jul;80(1):207–215. doi: 10.1172/JCI113049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pastoriza-Muñoz E., Colindres R. E., Lassiter W. E., Lechene C. Effect of parathyroid hormone on phosphate reabsorption in rat distal convolution. Am J Physiol. 1978 Oct;235(4):F321–F330. doi: 10.1152/ajprenal.1978.235.4.F321. [DOI] [PubMed] [Google Scholar]
  24. Pollock A. S., Warnock D. G., Strewler G. J. Parathyroid hormone inhibition of Na+-H+ antiporter activity in a cultured renal cell line. Am J Physiol. 1986 Feb;250(2 Pt 2):F217–F225. doi: 10.1152/ajprenal.1986.250.2.F217. [DOI] [PubMed] [Google Scholar]
  25. Preisig P. A., Ives H. E., Cragoe E. J., Jr, Alpern R. J., Rector F. C., Jr Role of the Na+/H+ antiporter in rat proximal tubule bicarbonate absorption. J Clin Invest. 1987 Oct;80(4):970–978. doi: 10.1172/JCI113190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ramsammy L. S., Josepovitz C., Kaloyanides G. J. Gentamicin inhibits agonist stimulation of the phosphatidylinositol cascade in primary cultures of rabbit proximal tubular cells and in rat renal cortex. J Pharmacol Exp Ther. 1988 Dec;247(3):989–996. [PubMed] [Google Scholar]
  27. Scoble J. E., Mills S., Hruska K. A. Calcium transport in canine renal basolateral membrane vesicles. Effects of parathyroid hormone. J Clin Invest. 1985 Apr;75(4):1096–1105. doi: 10.1172/JCI111803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vurek G. G., Warnock D. G., Corsey R. Measurement of picomole amounts of carbon dioxide by calorimetry. Anal Chem. 1975 Apr;47(4):765–767. doi: 10.1021/ac60354a024. [DOI] [PubMed] [Google Scholar]
  29. Weinman E. J., Shenolikar S. Protein kinase C activates the renal apical membrane Na+/H+ exchanger. J Membr Biol. 1986;93(2):133–139. doi: 10.1007/BF01870805. [DOI] [PubMed] [Google Scholar]
  30. Yoshitomi K., Frömter E. Cell pH of rat renal proximal tubule in vivo and the conductive nature of peritubular HCO3- (OH-) exit. Pflugers Arch. 1984 Nov;402(3):300–305. doi: 10.1007/BF00585513. [DOI] [PubMed] [Google Scholar]

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