AJP - Renal Add DOIs to your references at manuscript stage!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 293: F660-F661, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00260.2007
0363-6127/07 $8.00
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/F660    most recent
00260.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Verlander, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Verlander, J. W.

EDITORIAL FOCUS

The thiazide-sensitive NaCl cotransporter: a new target for acute regulation of salt and water transport by angiotensin II

Jill W. Verlander

Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida

THERE IS NO DOUBT ABOUT THE clinical importance of the thiazide-sensitive sodium chloride cotransporter (NCC). The NCC exists exclusively in the distal convoluted tubule and is responsible for 5–10% of NaCl reabsorption by the kidney. The efficacy of an inhibitor of the NCC, chlorothiazide, in lowering blood pressure was first demonstrated in 1958 (3), and thiazide diuretics continue to serve as a low-cost and effective drug for the treatment of hypertension in many patients. Genetic mutations in humans and mice that suppress or heighten NCC function cause hypotension or hypertension, respectively (10).

Despite the importance of NCC function in human health and nearly 50 years of clinical application of NCC inhibitors, the mechanisms of NCC action and regulation are only recently being defined. Thiazide diuretics were in clinical use for decades before physiological studies determined that the thiazide receptor was a NaCl cotransporter (8, 9, 14) and autoradiographic studies using tritiated metolazone binding localized the NCC to the distal convoluted tubule (2). The protein structure and gene sequence of the mammalian NCC were described only 13 years ago (11) and provided the tools for immunolocalization and gene expression studies. These not only confirmed that the NCC was located exclusively in the apical region of distal convoluted tubule cells (1, 19, 22) but also allowed examination of the mechanisms of its regulation.

The elegant work of Sandberg et al. (24) reports important new information about NCC regulation. They demonstrate three novel findings: 1) acute regulation of NCC apical plasma membrane expression in an animal model; 2) NCC regulation by intracellular trafficking; 3) effects induced by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril and ablated by infusion of captopril with angiotensin II (ANG II), thus suggesting direct regulation of NCC function by ANG II.

Sandberg et al. (24) demonstrate more rapid regulation of NCC than has been reported previously. Several investigators have shown changes in NCC abundance in experimental animals chronically fed low- or high-salt diets (17, 23), loaded with ammonium chloride (12), or treated with steroid hormones including mineralocorticoids (7, 13), glucocorticoids (7), and estradiol (30). Recently, With-No-Lysine[K] (WNK) kinases have been found to regulate NCC expression in Xenopus laevis oocytes (34), and mutations of WNK kinases in humans are associated with familial hyperkalemic hypertension (Gordon syndrome) (25, 33) and Gitelman's syndrome (10), genetic conditions associated with abnormally high and abnormally low NCC function, respectively. Salmon calcitonin and amylin infusions produce increased tritiated metolazone binding in renal homogenates within hours (4, 5). However, Sandberg et al. (24) observed a significant reduction in apical plasma membrane NCC within 20 min of exposure to captopril.

It is not surprising that such a rapid response occurs by intracellular trafficking of the NCC protein. Subcellular redistribution of other transport proteins and channels, such as aquaporin 2 (18), ENaC subunits (16), pendrin (26, 27), and H+-ATPase (28, 29), alters functional expression of transporters and thus regulates transport in other renal epithelial cell types, often without increasing total cellular expression. Although subcellular redistribution was not detected in previous studies that examined chronic regulation of NCC using immunolocalization (13, 30), WNK kinases appear to regulate NCC function in X. laevis oocytes, at least in part, by regulating NCC subcellular distribution (34), and defective membrane targeting of NCC has been observed in both Gitelman's (10) and Gordon syndromes (33). Nonetheless, subcellular redistribution of NCC has not been demonstrated previously in native cells.

Finally, the findings of Sandberg et al. (24) suggest that ANG II may directly control distribution of NCC to the apical plasma membrane in distal convoluted tubule cells. A previous study of mice fed a low-salt diet found reduced NCC protein in AT1a receptor knockouts compared with wild-type mice (6), thus demonstrating that normal NCC expression depends on ANG II stimulation. Several studies, both in vivo and in vitro, have shown that ANG II regulates transport or transporter distribution in other renal epithelial cells. ANG II stimulates sodium and bicarbonate uptake in the early distal tubule (32), apical ENaC activity in CCD principal cells (21), chloride uptake via pendrin in mouse CCD (20), and Na/H exchange and Na-HCO3 cotransport in the proximal tubule (15, 31). The evidence that ACE inhibition suppresses NCC-mediated NaCl transport adds important new knowledge about the direct effects of ANG II on renal epithelial transport and the mechanism of ACE inhibition in the control of blood pressure.

This work by Sandberg and colleagues (24) is the outcome of a carefully designed and executed animal model, the finest quality quantitative immunogold electron microscopy, and correlation with membrane fractionation studies. The animal studies were designed and conducted to determine the effects of captopril and captopril plus ANG II infusions without confounding changes in blood pressure or glomerular filtration rate. Although the membrane fractionation studies alone suggest that ANG II controls the subcellular distribution of NCC, microscopic localization of the transporter was warranted. However, immunofluorescence microscopy was inconclusive. Light microscopic methods, including confocal microscopy, are often inadequate to determine the precise subcellular location of proteins or to detect changes in distribution or abundance in subcellular compartments. The quantitative immunogold analysis performed on ultrathin cryosections and reported by Sandberg et al. represents not only exceptional technical expertise but also an exceptional effort and commitment to excellence to produce this work. As a result, these investigators convincingly and elegantly demonstrate a previously unknown renal response to ACE inhibition, that is, rapid internalization of NCC and thus acute suppression of NaCl uptake in the distal convoluted tubule.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Verlander, Div. of Nephrology, Hypertension, and Renal Transplantation, Univ. of Florida, Gainesville, FL 32610-0224 (e-mail: verlaj{at}medicine.ufl.edu)


   REFERENCES
TOP
 REFERENCES
 

  1. Bachmann S, Velazquez H, Obermuller N, Reilly RF, Moser D, Ellison DH. Expression of the thiazide-sensitive Na-Cl cotransporter by rabbit distal convoluted tubule cells. J Clin Invest 96: 2510–2514, 1995.[Web of Science][Medline]
  2. Beaumont K, Vaughn DA, Healy DP. Thiazide diuretic receptors: autoradiographic localization in rat kidney with [3H]metolazone. J Pharmacol Exp Ther 250: 414–419, 1989.[Abstract/Free Full Text]
  3. Beyer KH Jr, Baer JE, Russo HF, Noll R. Electrolyte excretion as influenced by chlorothiazide. Science 127: 146–147, 1958.[Free Full Text]
  4. Blakely P, Vaughn DA, Fanestil DD. Amylin, calcitonin gene-related peptide, and adrenomedullin: effects on thiazide receptor and calcium. Am J Physiol Renal Fluid Electrolyte Physiol 272: F410–F415, 1997.[Abstract/Free Full Text]
  5. Blakely P, Vaughn DA, Fanestil DD. Effects of calcium-modulating hormones on thiazide receptor density. J Am Soc Nephrol 7: 1052–1057, 1996.[Abstract]
  6. Brooks HL, Allred AJ, Beutler KT, Coffman TM, Knepper MA. Targeted proteomic profiling of renal Na+ transporter and channel abundances in angiotensin II type 1a receptor knockout mice. Hypertension 39: 470–473, 2002.[Abstract/Free Full Text]
  7. Chen Z, Vaughn DA, Blakely P, Fanestil DD. Adrenocortical steroids increase renal thiazide diuretic receptor density and response. J Am Soc Nephrol 5: 1361–1368, 1994.[Abstract]
  8. Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol Renal Fluid Electrolyte Physiol 248: F527–F535, 1985.[Abstract/Free Full Text]
  9. Ellison DH, Velazquez H, Wright FS. Thiazide-sensitive sodium chloride cotransport in early distal tubule. Am J Physiol Renal Fluid Electrolyte Physiol 253: F546–F554, 1987.[Abstract/Free Full Text]
  10. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 85: 423–493, 2005.[Abstract/Free Full Text]
  11. Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, Hebert SC. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722, 1994.[Abstract/Free Full Text]
  12. Kim GH, Martin SW, Fernandez-Llama P, Masilamani S, Packer RK, Knepper MA. Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake. Am J Physiol Renal Physiol 279: F459–F467, 2000.[Abstract/Free Full Text]
  13. Kim GH, Masilamani S, Turner R, Mitchell C, Wade JB, Knepper MA. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci USA 95: 14552–14557, 1998.[Abstract/Free Full Text]
  14. Kunau RT Jr, Weller DR, Webb HL. Clarification of the site of action of chlorothiazide in the rat nephron. J Clin Invest 56: 401–407, 1975.[Web of Science][Medline]
  15. Liu FY, Cogan MG. Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule: modes of action, mechanism, and kinetics. J Clin Invest 82: 601–607, 1988.[Web of Science][Medline]
  16. Loffing J, Pietri L, Aregger F, Bloch-Faure M, Ziegler U, Meneton P, Rossier BC, Kaissling B. Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets. Am J Physiol Renal Physiol 279: F252–F258, 2000.[Abstract/Free Full Text]
  17. Masilamani S, Wang X, Kim GH, Brooks H, Nielsen J, Nielsen S, Nakamura K, Stokes JB, Knepper MA. Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction. Am J Physiol Renal Physiol 283: F648–F657, 2002.[Abstract/Free Full Text]
  18. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA. Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA 92: 1013–1017, 1995.[Abstract/Free Full Text]
  19. Obermuller N, Bernstein P, Velazquez H, Reilly R, Moser D, Ellison DH, Bachmann S. Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. Am J Physiol Renal Fluid Electrolyte Physiol 269: F900–F910, 1995.[Abstract/Free Full Text]
  20. Pech V, Kim YH, Weinstein AM, Everett LA, Pham TD, Wall SM. Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism. Am J Physiol Renal Physiol 292: F914–F920, 2007.[Abstract/Free Full Text]
  21. Peti-Peterdi J, Warnock DG, Bell PD. Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT1 receptors. J Am Soc Nephrol 13: 1131–1135, 2002.[Abstract/Free Full Text]
  22. Plotkin MD, Kaplan MR, Verlander JW, Lee WS, Brown D, Poch E, Gullans SR, Hebert SC. Localization of the thiazide sensitive Na-Cl cotransporter, rTSC1 in the rat kidney. Kidney Int 50: 174–183, 1996.[Web of Science][Medline]
  23. Sandberg MB, Maunsbach AB, McDonough AA. Redistribution of distal tubule Na+-Cl– cotransporter in response to a high-salt diet. Am J Physiol Renal Physiol 291: F503–F508, 2006.[Abstract/Free Full Text]
  24. Sandberg MB, Riquier AD, Pihakaski-Maunsbach K, McDonough AA, Maunsbach AB. Angiotensin II provokes acute trafficking of distal tubule Na+-Cl– cotransporter to apical membrane. Am J Physiol Renal Physiol. First published May 16, 2007; doi:10.1152/ajprenal.00064.2007.
  25. Subramanya AR, Yang CL, McCormick JA, Ellison DH. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Kidney Int 70: 630–634, 2006.[CrossRef][Web of Science][Medline]
  26. Verlander JW, Hassell KA, Royaux IE, Glapion DM, Wang ME, Everett LA, Green ED, Wall SM. Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension. Hypertension 42: 356–362, 2003.[Abstract/Free Full Text]
  27. Verlander JW, Kim YH, Shin W, Pham TD, Hassell KA, Beierwaltes WH, Green ED, Everett L, Matthews SW, Wall SM. Dietary Cl– restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells. Am J Physiol Renal Physiol 291: F833–F839, 2006.[Abstract/Free Full Text]
  28. Verlander JW, Madsen KM, Cannon JK, Tisher CC. Activation of acid-secreting intercalated cells in rabbit collecting duct with ammonium chloride loading. Am J Physiol Renal Fluid Electrolyte Physiol 266: F633–F645, 1994.[Abstract/Free Full Text]
  29. Verlander JW, Madsen KM, Galla JH, Luke RG, Tisher CC. Response of intercalated cells to chloride depletion metabolic alkalosis. Am J Physiol Renal Fluid Electrolyte Physiol 262: F309–F319, 1992.[Abstract/Free Full Text]
  30. Verlander JW, Tran TM, Zhang L, Kaplan MR, Hebert SC. Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest 101: 1661–1669, 1998.[Web of Science][Medline]
  31. Wagner CA, Giebisch G, Lang F, Geibel JP. Angiotensin II stimulates vesicular H+-ATPase in rat proximal tubular cells. Proc Natl Acad Sci USA 95: 9665–9668, 1998.[Abstract/Free Full Text]
  32. Wang T, Giebisch G. Effects of angiotensin II on electrolyte transport in the early and late distal tubule in rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 271: F143–F149, 1996.[Abstract/Free Full Text]
  33. Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA 100: 680–684, 2003.[Abstract/Free Full Text]
  34. Yang CL, Zhu X, Wang Z, Subramanya AR, Ellison DH. Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. J Clin Invest 115: 1379–1387, 2005.[CrossRef][Web of Science][Medline]




This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/F660    most recent
00260.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Verlander, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Verlander, J. W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.