Preferences help
enabled [disable] Abstract
Number of results
2004 | 51 | 3 | 757-772
Article title

Bidirectional regulation of renal cortical Na+,K+-ATPase by protein kinase C.

Title variants
Languages of publication
We examined the role of protein kinase C (PKC) in the regulation of Na+,K+- ATPase activity in the renal cortex. Male Wistar rats were anaesthetized and the investigated reagents were infused into the abdominal aorta proximally to the renal arteries. A PKC-activating phorbol ester, phorbol 12,13-dibutyrate (PDBu), had a dose-dependent effect on cortical Na+,K+-ATPase activity. Low dose of PDBu (10-11 mol/kg per min) increased cortical Na+,K+-ATPase activity by 34.2%, whereas high doses (10-9 and 10-8 mol/kg per min) reduced this activity by 22.7% and 35.0%, respectively. PDBu administration caused changes in Na+,K+-ATPase Vmax without affecting K0.5 for Na+, K+ and ATP as well as Ki for ouabain. The effects of PDBu were abolished by PKC inhibitors, staurosporine, GF109203X, and Gö 6976. The inhibitory effect of PDBu was reversed by pretreatment with inhibitors of cytochrome P450-dependent arachidonate metabolism, ethoxyresorufin and 17-octadecynoic acid, inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin and LY294002, and by actin depolymerizing agents, cytochalasin D and latrunculin B. These results suggest that PKC may either stimulate or inhibit renal cortical Na+,K+-ATPase. The inhibitory effect is mediated by cytochrome P450-dependent arachidonate metabolites and PI3K, and is caused by redistribution of the sodium pump from the plasma membrane to the inactive intracellular pool.
Physical description
  • Department of Pathophysiology, Medical University, Lublin, Poland
  • Department of Pathophysiology, Medical University, Lublin, Poland
  • Department of Pathophysiology, Medical University, Lublin, Poland
  • Department of Pathophysiology, Medical University, Lublin, Poland
  • Department of Pathophysiology, Medical University, Lublin, Poland
  • Bełtowski J, Görny D, Marciniak A. (1998) Biphasic effect of protein kinase C on rat renal cortical Na+,K+ -ATPase. J Physiol Pharmacol.; 49: 627-39.
  • Bełtowski J, Marciniak A, Wójcicka G, Görny D. (2003a) Regulation of renal Na+,K+-ATPase and ouabain-sensitive H+,K+-ATPase by the cyclic AMP-protein kinase A signal transduction pathway. Acta Biochim Polon.; 50: 103-14.
  • Bełtowski J, Wójcicka G. (2002) Spectrophotometric method for the determination of renal ouabain-sensitive H+,K+-ATPase activity. Acta Biochim Polon.; 49: 515-27.
  • Bełtowski J, Marciniak A, Wójcicka G, Görny D. (2003b) Nitric oxide decreases renal medullary Na+,K+-ATPase activity through cyclic GMP-protein kinase G dependent mechanism. J Physiol Pharmacol.; 54: 191-210.
  • Belusa R, Wang ZM, Matsubara T, Sahlgren B, Dulubova I, Nairn AC, Ruoslahti E, Greengard P, Aperia A. (1997) Mutation of the protein kinase C phosphorylation site on rat α1 Na+,K+-ATPase alters regulation of intracellular Na+ and pH and influences cell shape and adhesiveness. J Biol Chem.; 272: 20179-84.
  • Beron J, Forster I, Beguin P, Geering K, Verrey F. (1997) Phorbol 12-myristate 13-acetate down-regulates Na+,K+-ATPase independent of its protein kinase C site: decrease in basolateral cell surface area. Mol Biol Cell.; 8: 387-98.
  • Bertorello A, Aperia A. (1989) Na+,K+-ATPase is an effector protein for protein kinase C in renal proximal tubule cells. Am J Physiol.; 256: F370-3.
  • Bertorello AM, Aperia A, Walaas SI, Nairn AC, Greengard P. (1991) Phosphorylation of the catalytic subunit of Na+,K+-ATPase inhibits the activity of the enzyme. Proc Natl Acad Sci USA.; 88: 11359-62.
  • Blanco G, Sanchez G, Mercer RW. (1998) Differential regulation of Na+,K+-ATPase isozymes by protein kinases and arachidonic acid. Arch Biochem Biophys.; 359: 139-50.
  • Budu CE, Efendiev R, Cinelli AM, Bertorello AM, Pedemonte CH. (2002) Hormonal-dependent recruitment of Na+,K+-ATPase to the plasmalemma is mediated by PKCβ and modulated by [Na+]i. Br J Pharmacol.; 137: 1380-6.
  • Carranza ML, Feraille E, Favre H. (1996) Protein kinase C-dependent phosphorylation of Na+,K+-ATPase α-subunit in rat kidney cortical tubules. Am J Physiol.; 271: C136-43.
  • Chibalin AV, Katz AI, Berggren PO, Bertorello AM. (1997) Receptor-mediated inhibition of renal Na+,K+-ATPase is associated with endocytosis of its α- and β-subunits. Am J Physiol.; 273: C1458-65.
  • Chibalin AV, Pedemonte CH, Katz AI, Feraille E, Berggren PO, Bertorello AM. (1998a) Phosphorylation of the catalytic alpha-subunit constitutes a triggering signal for Na+,K+-ATPase endocytosis. J Biol Chem.; 273: 8814-9.
  • Chibalin AV, Zierath JR, Katz AI, Berggren PO, Bertorello AM. (1998b) Phosphatidylinositol 3-kinase-mediated endocytosis of renal Na+,K+-ATPase α subunit in response to dopamine. Mol Biol Cell.; 9: 1209-20.
  • Chibalin AV, Ogimoto G, Pedemonte CH, Pressley TA, Katz AI, Feraille E, Berggren PO, Bertorello AM. (1999) Dopamine-induced endocytosis of Na+,K+-ATPase is initiated by phosphorylation of Ser-18 in the rat alpha subunit and is responsible for the decreased activity in epithelial cells. J Biol Chem.; 274: 1920-7.
  • De Camilli P, Emr SD, McPherson PS, Novick P. (1996) Phosphoinositides as regulators in membrane traffic. Science.; 271: 1533-9.
  • Efendiev R, Bertorello AM, Pedemonte CH. (1999) PKC-β and PKC-ζ mediate opposing effects on proximal tubule Na+,K+-ATPase activity. FEBS Lett.; 456: 45-8.
  • Efendiev R, Bertorello AM, Pressley TA, Rousselot M, Feraille E, Pedemonte CH. (2000) Simultaneous phosphorylation of Ser11 and Ser18 in the alpha-subunit promotes the recruitment of Na+,K+-ATPase molecules to the plasma membrane. Biochemistry.; 39: 9884-92.
  • Efendiev R, Bertorello AM, Zandomeni R, Cinelli AR, Pedemonte CH. (2002) Agonist-dependent regulation of renal Na+,K+-ATPase activity is modulated by intracellular sodium concentration. J Biol Chem.; 277: 11489-96.
  • Feraille E, Carranza ML, Buffin-Meyer B, Rousselot M, Doucet A, Favre H. (1995) Protein kinase C-dependent stimulation of Na+,K+-ATPase in rat proximal convoluted tubules. Am J Physiol.; 268: C1277-83.
  • Feraille E, Beguin P, Carranza ML, Gonin S, Rousselot M, Martin PY, Favre H, Geering K. (2000) Is phosphorylation of the alpha1 subunit at Ser-16 involved in the control of Na+,K+-ATPase activity by phorbol ester-activated protein kinase C? Mol Biol Cell.; 11: 39-50.
  • Feraille E, Doucet A. (2001) Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: Hormonal control. Physiol Rev.; 81: 345-418.
  • Feschenko MS, Sweadner KJ. (1995) Structural basis for species-specific differences in the phosphorylation of Na,K-ATPase by protein kinase C. J Biol Chem.; 270: 14072-7.
  • Feschenko MS, Sweadner KJ. (1997) Phosphorylation of Na,K-ATPase by protein kinase C at Ser18 occurs in intact cells but does not result in direct inhibition of ATP hydrolysis. J Biol Chem.; 272: 17726-33.
  • Gomes P, Soares-da-Silva P. (2002) Dopamine-induced inhibition of Na+,K+-ATPase activity requires integrity of actin cytoskeleton in opossum kidney cells. Acta Physiol Scand.; 175: 93-101.
  • Gonin S, Deschenes G, Roger F, Bens M, Martin PY, Carpentier JL, Vandewalle A, Doucet A, Feraille E. (2001) Cyclic AMP increases cell surface expression of functional Na+,K+-ATPase units in mammalian cortical collecting duct principal cells. Mol Biol Cell.; 12: 255-64.
  • Hofmann J. (1997) The potential for isoenzyme-selective modulation of protein kinase C. FASEB J.; 11: 649-69.
  • Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science.; 272: 728-31.
  • Karim Z, Defontaine N, Paillard M, Poggioli J. (1995) Protein kinase C isoforms in rat kidney proximal tubule: acute effect of angiotensin II. Am J Physiol.; 269: C134-40.
  • Karim ZG, Chambrey R, Chalumeau C, Defontaine N, Warnock DG, Paillard M, Poggioli J. (1999) Regulation by PKC isoforms of Na+/H+ exchanger in luminal membrane vesicles isolated from cortical tubules. Am J Physiol.; 277: F773-8.
  • Kazanietz MG, Caloca MJ, Aizman O, Nowicki S. (2001) Phosphorylation of the catalytic subunit of rat renal Na+,K+-ATPase by classical PKC isoforms. Arch Biochem Biophys.; 388: 74-80.
  • Kiroytscheva M, Cheval L, Carranza ML, Martin PY, Favre H, Doucet A, Feraille E. (1999) Effect of cAMP on the activity and the phosphorylation of Na+,K+-ATPase in rat thick ascending limb of Henle. Kidney Int.; 55: 1819-31.
  • Kowluru RA, Jirousek MR, Stramm L, Farid N, Engerman RL, Kern TS. (1998) Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPases. Diabetes.; 47: 464-9.
  • Lamaze C, Fujimoto LM, Yin HL, Schmid SL. (1997) The actin cytoskeleton is required for receptor-mediated endocytosis in mammalian cells. J Biol Chem.; 272: 20332-5.
  • Li G, D'Souza-Schorey S, Barbieri MA, Roberts RL, Klippel A, Williams LT, Stahl PD. (1995) Evidence for phosphatidylinositol 3-kinase as a regulator of endocytosis via activation of Rab5. Proc Natl Acad Sci USA.; 92: 10207-11.
  • Logvinenko NS, Dulubova I, Fedosova N, Larsson SH, Nairn AC, Esmann M, Greengard P, Aperia A. (1996) Phosphorylation by protein kinase C of serine-23 of the alpha-1 subunit of rat Na+,K+-ATPase affects its onformational equilibrium. Proc Natl Acad Sci.; 93: 9132-7.
  • Lowry OH, Rosebrough NI, Farr AL, Randall RJ. (1951) Protein measurement with the Folin phenol reagent. J Biol Chem.; 193: 265-75.
  • Mahmmoud YA, Vorum H, Cornelius F. (2000) Identification of a phospholemman-like protein from shark rectal glands. Evidence for indirect regulation of Na+,K+-ATPase by protein kinase C via a novel member of the FXYDY family. J Biol Chem.; 275: 35969-77.
  • Middleton JP, Khan WA, Collinsworth G, Hannun YA, Medford RM. (1993) Heterogeneity of protein kinase C-mediated rapid regulation of Na/K-ATPase in kidney epithelial cells. J Biol Chem.; 268: 15958-64.
  • Nishizuka Y. (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J.; 9: 484-96.
  • Nowicki S, Chen SL, Aizman O, Cheng XJ, Li D, Nowicki C, Nairn A, Greengard P, Aperia A. (1997) 20-Hydroxyeicosatetraenoic acid (20-HETE) activates protein kinase C. Role in regulation of rat renal Na+,K+-ATPase. J Clin Invest.; 99: 1224-30.
  • Ominato M, Satoh T, Katz AI. (1996) Regulation of Na+,K+-ATPase activity in the proximal tubule: role of the protein kinase C pathway and of eicosanoids. J Membr Biol.; 152: 235-43.
  • Ostlund E, Mendez CF, Jacobsson G, Fryckstedt J, Meister B, Aperia A. (1995) Expression of protein kinase C isoforms in renal tissue. Kidney Int.; 47: 766-73.
  • Padanilam BJ. (2001) Induction and subcellular localization of protein kinase C isozymes following renal ischemia. Kidney Int.; 59: 1789-97.
  • Pedemonte CH, Pressley TA, Cinelli AR, Lokhandwala MF. (1997a) Stimulation of protein kinase C rapidly reduces intracellular Na+ concentration via activation of the Na+ pump in OK cells. Mol Pharmacol.; 52: 88-97.
  • Pedemonte CH, Pressley TA, Lokhandwala MF, Cinelli AR. (1997b) Regulation of Na+,K+-ATPase transport activity by protein kinase C. J Membr Biol.; 155: 219-27.
  • Pfaff IL, Wagner HJ, Vallon V. (1999) Immunolocalization of protein kinase C isoenzymes α, β1 and βII in rat kidney. J Am Soc Nephrol.; 10: 1861-73.
  • Ron D, Kazanietz MG. (1999) New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB J.; 13: 1658-76.
  • Satoh T, Cohen HT, Katz AI. (1993) Different mechanisms of renal Na+,K+-ATPase regulation by protein kinases in proximal and distal nephron. Am J Physiol.; 265: F399-405.
  • Serlachius E, Svennilson J, Schalling M, Aperia A. (1997) Protein kinase C in the developing kidney: isoform expression and effects of ceramide and PKC inhibitors. Kidney Int.; 52: 901-10.
  • Tsimaratos M, Roger F, Chabardes D, Mordasini D, Hasler U, Doucet A, Martin PY, Feraille E. (2003) C-peptide stimulates Na+,K+-ATPase activity via PKCα in rat medullary thick ascending limb. Diabetologia.; 46: 124-31.
  • Vinciguerra M, Deschenes G, Hasler U, Mordasini D, Rousselot M, Doucet A, Vandewalle A, Martin PY, Feraille E. (2003) Intracellular Na+ controls cell surface expression of Na,K-ATPase via a cAMP-independent PKA pathway in mammalian kidney collecting duct cells. Mol Biol Cell.; 14: 2677-88.
  • Wang T. (1997) Nitric oxide regulates HCO3- and Na+ transport by a cGMP-mediated mechanism in the kidney proximal tubule. Am J Physiol.; 272: F242-8.
  • Wilborn TW, Schafer JA. (1996) Differential expression of PKC isoforms in fresh and cultured rabbit CCD. Am J Physiol.; 270: F766-75.
  • Yao LP, Li XX, Yu PY, Xu J, Asico LD, Jose PA. (1998) Dopamine D1 receptor and protein kinase C isoforms in spontaneously hypertensive rats. Hypertension.; 32: 1049-53.
  • Yudowski GA, Efendiev R, Pedemonte CH, Katz AI, Berggren PO, Bertorello AM. (2000) Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+,K+-ATPase α subunit and regulates its trafficking. Proc Natl Acad Sci USA.; 97: 6556-61.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.