Collecting Duct Renin: A Critical Linkin Angiotensin II-Dependent Hypertension

  • Minolfa C. Prieto
  • L. Gabriel Navar
Conference paper


All of the components needed for angiotensin II generation are present within the renal tubular network of the kidney. This brief review is focused on recent evidence demonstrating that inappropriate activation of renin in distal nephron segments by acting on angiotensinogen generated in the proximal tubule cells and delivered to the distal nephron may contribute to increased distal intrarenal angiotensin II formation, sodium retention, and development and progression of hypertension. Moreover, mechanisms regulating collecting duct renin during Ang II-dependent hypertension are discussed.


Angiotensin Converting Enzyme Principal Cell Distal Nephron Collect Duct Cell Angiotensin Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Research performed by the authors has been supported by grants from National Heart, Lung, and Blood Institute Grant HL-26731, National Institutes of Health Grant P20-RR-017659 from the Institutional Developmental Award (IdeA) program of NCRR, Eunice Kennedy Shriver National Institute of Child Health & Human Development Grant K12HD043451, and the Louisiana Board of Regents Millennium Health Excellence Fund (2001-06-07).


  1. 1.
    Ferrario CM. Contribution of angiotensin-(1-7) to cardiovascular physiology and pathology. Curr Hypertens Rep. 2003;5(2):129–134.PubMedCrossRefGoogle Scholar
  2. 2.
    Imig JD, Navar GL, Zou LX, et al. Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors. Am J Physiol-Renal Physiol. 1999;277:F303–F311.Google Scholar
  3. 3.
    Ingert C, Grima M, Coquard C, Barthelmebs M, Imbs JL. Contribution of angiotensin II internalization to intrarenal angiotensin II levels in rats. Am J Physiol Renal Physiol. 2002;283(5):F1003–F1010.PubMedGoogle Scholar
  4. 4.
    van Kats JP, Schalekamp MA, Verdouw PD, Duncker DJ, Danser AH. Intrarenal angiotensin II: interstitial and cellular levels and site of production. Kidney Int. 2001;60(6):2311–2317.CrossRefGoogle Scholar
  5. 5.
    Re RN. The intracrine hypothesis and intracellular peptide hormone action. Bioessays. 2003;25(4):401–409.PubMedCrossRefGoogle Scholar
  6. 6.
    Von Thun AM, Vari RC, El-Dahr SS, Navar LG. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion. Am J Physiol-Renal Physiol. 1994;266:F120–F128.Google Scholar
  7. 7.
    Zou LX, Hymel A, Imig JD, Navar LG. Renal accumulation of circulating angiotensin II in angiotensin II-infused rats. Hypertension. 1996;27:658–662.PubMedGoogle Scholar
  8. 8.
    Kobori H, Harrison-Bernard LM, Navar LG. Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production. Kidney Int. 2002;61(2):579–585.PubMedCrossRefGoogle Scholar
  9. 9.
    Kobori H, Harrison-Bernard LM, Navar LG. Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension. J Am Soc Nephrol. 2001;12:431–439.PubMedGoogle Scholar
  10. 10.
    Mitchell KD, Jacinto SM, Mullins JJ. Proximal tubular fluid, kidney, and plasma levels of angiotensin II in hypertensive ren-2 transgenic rats. Am J Physiol-Renal Physiol. 1997;273:F246–F253.Google Scholar
  11. 11.
    Navar LG, Lewis L, Hymel A, Braam B, Mitchell KD. Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats. J Am Soc Nephrol. 1994;5:1153–1158.PubMedGoogle Scholar
  12. 12.
    Rohrwasser A, Morgan T, Dillon HF, et al. Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension. 1999;34(6):1265–1274.PubMedGoogle Scholar
  13. 13.
    Prieto-Carrasquero MC, Harrison-Bernard LM, Kobori H, et al. Enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Hypertension. 2004;44(2):223–229.PubMedCrossRefGoogle Scholar
  14. 14.
    Kang JJ, Toma I, Sipos A, Meer EJ, Vargas SL, Peti-Peterdi J. The collecting duct is the major source of prorenin in diabetes. Hypertension. 2008;51(6):1597–1604.PubMedCrossRefGoogle Scholar
  15. 15.
    Casarini DE, Boim MA, Stella RCR, Krieger-Azzolini MH, Krieger JE, Schor N. Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron. Am J Physiol-Renal Physiol. 1997;272:F405–F409.Google Scholar
  16. 16.
    Redublo Quinto BM, Camargo de Andrade MC, Ronchi FA, et al. Expression of angiotensin I-converting enzymes and bradykinin B2 receptors in mouse inner medullary-collecting duct cells. Int Immunopharmacol. 2008;8(2):254–260.CrossRefGoogle Scholar
  17. 17.
    Zou L, Hymel A, Imig JD, Navar LG. Renal accumulation of circulating angiotensin II in angiotensin II-infused rats. Hypertension. 1996;27 (part 2):658–662.PubMedGoogle Scholar
  18. 18.
    Zhuo JL, Imig JD, Hammond TG, Orengo S, Benes E, Navar LG. Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT(1) receptor. Hypertension. 2002;39(1):116–121.PubMedCrossRefGoogle Scholar
  19. 19.
    Gonzalez-Villalobos R, Klassen RB, Allen PL, Navar LG, Hammond TG. Megalin binds and internalizes angiotensin II. Am J Physiol Renal Physiol. 2005;288(2):F420–F427.PubMedCrossRefGoogle Scholar
  20. 20.
    Zou LX, Imig JD, Von Thun AM, Hymel A, Ono H, Navar LG. Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II-infused rats. Hypertension. 1996;28:669–677.PubMedGoogle Scholar
  21. 21.
    Gonzalez-Villalobos RA, Seth DM, Satou R, et al. Intrarenal angiotensin II and angiotensinogen augmentation in chronic angiotensin II-infused mice. Am J Physiol Renal Physiol. 2008;295(3):F772–F779.PubMedCrossRefGoogle Scholar
  22. 22.
    Schunkert H, Ingelfinger JR, Jacob H, Jackson B, Bouyounes B, Dzau VJ. Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II. Am J Physiol-Endocrinol Metab. 1992;263:E863–E869.Google Scholar
  23. 23.
    Ingelfinger JR, Jung F, Diamant D, et al. Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback. Am J Physiol-Renal Physiol. 1999;276:F218–F227.Google Scholar
  24. 24.
    Kobori H, Nishiyama A, Harrison-Bernard LM, Navar LG. Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension. Hypertension. 2003;41(1):42–49.PubMedCrossRefGoogle Scholar
  25. 25.
    Ding Y, Davisson RL, Hardy DO, et al. The kidney androgen-regulated protein promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice. J Biol Chem. 1997;272:28142–28148.PubMedCrossRefGoogle Scholar
  26. 26.
    Davisson RL, Ding Y, Stec DE, Catterall JF, Sigmund CD. Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice. Physiol Genomics. 1999;1:3–9.PubMedGoogle Scholar
  27. 27.
    Taugner R, Hackenthal E, Inagami T, Nobiling R, Poulsen K. Vascular and tubular renin in the kidneys of mice. Histochemistry. 1982;75(4):473–484.PubMedGoogle Scholar
  28. 28.
    Dzau VJ. Significance of the vascular renin-angiotensin pathway. Hypertension. 1986; 8(7): 553–559.PubMedGoogle Scholar
  29. 29.
    Inagami T, Okamura T, Clemens D, Celio MR, Naruse K, Naruse M. Local generation of angiotensin in the kidney and in tissue culture. Clin Exp Hypertens A. 1983;5(7–8):1137–1149.PubMedCrossRefGoogle Scholar
  30. 30.
    Henrich WL, McAllister EA, Eskue A, Miller T, Moe OW. Renin regulation in cultured proximal tubular cells. Hypertension. 1996;27:1337–1340.PubMedGoogle Scholar
  31. 31.
    Moe OW, Ujiie K, Star RA, et al. Renin expression in renal proximal tubule. J Clin Invest. 1993;91:774–779.PubMedCrossRefGoogle Scholar
  32. 32.
    Prieto-Carrasquero MC, Kobori H, Ozawa Y, Gutierrez A, Seth D, Navar LG. AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Am J Physiol Renal Physiol. 2005;289:F632–F637.PubMedCrossRefGoogle Scholar
  33. 33.
    Peti-Peterdi J, Fintha A, Fuson AL, Tousson A, Chow RH. Real-time imaging of renin release in vitro. Am J Physiol Renal Physiol. 2004;287(2):F329–F335.PubMedCrossRefGoogle Scholar
  34. 34.
    Peti-Peterdi J. Multiphoton imaging of renal tissues in vitro. Am J Physiol Renal Physiol. 2005;288(6):F1079–F1083.PubMedCrossRefGoogle Scholar
  35. 35.
    Rohrwasser A, Ishigami T, Gociman B, et al. Renin and kallikrein in connecting tubule of mouse. Kidney Int. 2003;64(6):2155–2162.PubMedCrossRefGoogle Scholar
  36. 36.
    Prieto-Carrasquero MC, Botros FT, Pagan J, et al. Collecting duct renin is upregulated in both kidneys of 2-kidney, 1-clip goldblatt hypertensive rats. Hypertension. 2008;51(6):1590–1596.PubMedCrossRefGoogle Scholar
  37. 37.
    Danser AHJ, van Kats JP, Admiraal PJJ, et al. Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis. Hypertension. 1994;24:37–48.PubMedGoogle Scholar
  38. 38.
    Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002;109(11):1417–1427.PubMedGoogle Scholar
  39. 39.
    Catanzaro DF. Physiological relevenace of renin/prorenin binding and uptake. Hypertens Res. 28, 97–105. 2005.PubMedCrossRefGoogle Scholar
  40. 40.
    Krebs C, Hamming I, Sadaghiani S, et al. Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. Kidney Int. 2007;72:725–730.PubMedCrossRefGoogle Scholar
  41. 41.
    Prieto-Carrasquero MC, Botros FT, Martin VL, et al. Prorenin receptor in distal nephron segments of 2K1C Goldblatt hypertensive rats. Hypertension. 2008;52(4):e34–131.CrossRefGoogle Scholar
  42. 42.
    Nguyen G. Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor? Kidney Int. 2006;70(4):618–620.PubMedCrossRefGoogle Scholar
  43. 43.
    Siragy HM, Carey RM. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension. 1999;33:1237–1242.PubMedGoogle Scholar
  44. 44.
    Nishiyama A, Seth DM, Navar LG. Renal interstitial fluid angiotensin I and angiotensin II concentrations during local angiotensin-converting enzyme inhibition. J Am Soc Nephrol. 2002;13(9):2207–2212.PubMedCrossRefGoogle Scholar
  45. 45.
    Mendelsohn FAO. Failure of suppression of intrarenal angiotensin II in the contralateral kidney of one clip, two kidney hypertensive rats. Clin Exp Pharmacol Physiol. 1980;7:219–223.PubMedCrossRefGoogle Scholar
  46. 46.
    Morishita R, Higaki J, Okunishi H, et al. Changes in gene expression of the renin-angiotensin system in two-kidney, one clip hypertensive rats. J Hypertens. 1991;9:187–192.PubMedCrossRefGoogle Scholar
  47. 47.
    Guan S, Fox J, Mitchell KD, Navar LG. Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats. Hypertension. 1992;20:763–767.PubMedGoogle Scholar
  48. 48.
    Kobori H, Harrison-Bernard LM, Navar LG. Enhancement of angiotensinogen expression in angiotensin II-dependent hypertension. Hypertension. 2001;37:1329–1335.PubMedGoogle Scholar
  49. 49.
    Zou L, Imig JD, Von Thun AM, Hymel A, Ono H, Navar LG. Receptor-mediated intrarenal ANG II augmentation in ANG II-infused rats. Hypertension. 1996;28:669–677.PubMedGoogle Scholar
  50. 50.
    Cervenka L, Wang C-T, Mitchell KD, Navar LG. Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats. Hypertension. 1999;33:102–107.PubMedGoogle Scholar
  51. 51.
    Navar LG, Imig JD, Zou L, Wang C-T. Intrarenal production of angiotensin II. Sem Nephrol. 1997;17:412–422.Google Scholar
  52. 52.
    Harrison-Bernard LM, Zhuo J, Kobori H, Ohishi M, Navar LG. Intrarenal AT(1) receptor and ACE binding in ANG II-induced hypertensive rats. Am J Physiol Renal Physiol. 2002;282(1):F19–F25.PubMedGoogle Scholar
  53. 53.
    Pendergrass KD, Averill DB, Ferrario CM, Diz DI, Chappell MC. Differential expression of nuclear AT1 receptors and angiotensin II within the kidney of the male congenic mRen2.Lewis rat. Am J Physiol Renal Physiol. 2006;290(6):F1497–F1506.PubMedCrossRefGoogle Scholar
  54. 54.
    Lely AT, Hamming I, van Goor H, Navis GJ. Renal ACE2 expression in human kidney disease. J Pathol. 2004;204(5):587–593.PubMedCrossRefGoogle Scholar
  55. 55.
    Brosnihan KB, Neves LA, Joyner J, et al. Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy. Hypertension. 2003;42(4):749–753.PubMedCrossRefGoogle Scholar
  56. 56.
    Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–976.PubMedCrossRefGoogle Scholar
  57. 57.
    Gallagher PE, Chappell MC, Ferrario CM, Tallant EA. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol. 2006;290(2):C420–C426.PubMedCrossRefGoogle Scholar
  58. 58.
    Koka V, Huang XR, Chung ACK, Wang W, Truong LD, Lan HY. Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway. Am J Pathol. 2008;172(5):1174–1183.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Minolfa C. Prieto
    • 1
  • L. Gabriel Navar
    • 1
  1. 1.Department of PhysiologyTulane University Health Sciences CenterNew OrleansUSA

Personalised recommendations