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In hypertension, the kidney breaks your heart

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Abstract

The renin-angiotensin system (RAS) is a master regulator of blood pressure and fluid homeostasis. Because RAS components are expressed in several tissues that may influence blood pressure, studies using conventional gene targeting to globally interrupt the RAS have not determined the contributions of angiotensin II receptor type 1 (AT1) receptors in specific tissue pools to blood pressure regulation and tissue injury. Recent experiments using kidney cross-transplantation and mice lacking the dominant murine AT1 receptor isoform, AT 1A, have demonstrated that 1) AT1 receptors inside and outside the kidney make equivalent contributions to normal blood pressure homeostasis, 2) activation of renal AT 1 receptors is required for the development of angiotensin II-dependent hypertension, and 3) this blood pressure elevation rather than activation of AT1 receptors in the heart drives angiotensin II-induced cardiac hypertrophy. These findings, together with previous experiments, confirm the kidney’s critical role in the pathogenesis of hypertension and its complications.

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References and Recommended Reading

  1. Guyton AC: Blood pressure control-special role of the kidneys and body fluids. Science 1991, 252:1813–1816.

    Article  PubMed  CAS  Google Scholar 

  2. Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001, 104:545–556.

    Article  PubMed  CAS  Google Scholar 

  3. Husain A, Graham R, eds: Drugs, Enzymes and Receptors of the Renin-Angiotensin System: Celebrating a Century of Discovery, vol 1. Sidney: Harwood Academic; 2000.

    Google Scholar 

  4. Ito M, Oliverio MI, Mannon PJ, et al.: Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A 1995, 92:3521–3525.

    Article  PubMed  CAS  Google Scholar 

  5. Kim HS, Krege JH, Kluckman KD, et al.: Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci U S A 1995, 92:2735–2739.

    Article  PubMed  CAS  Google Scholar 

  6. Esther CR Jr, Howard TE, Marino EM, et al.: Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 1996, 74:953–965.

    PubMed  CAS  Google Scholar 

  7. Yanai K, Saito T, Kakinuma Y, et al.: Renin-dependent cardiovascular functions and renin-independent blood-brain barrier functions revealed by renin-deficient mice. J Biol Chem 2000, 275:5–8.

    Article  PubMed  CAS  Google Scholar 

  8. Shanmugam S, Sandberg K: Ontogeny of angiotensin II receptors. Cell Biol Int 1996, 20:169–176.

    Article  PubMed  CAS  Google Scholar 

  9. Timmermans PB, Wong PC, Chiu AT, et al.: Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993, 45:205–251.

    PubMed  CAS  Google Scholar 

  10. Tharaux PL, Coffman TM: Transgenic mice as a tool to study the renin-angiotensin system. Contrib Nephrol 2001, (135): 72–91.

    Google Scholar 

  11. Murphy TJ, Alexander RW, Griendling KK, et al.: Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 1991, 351:233–236.

    Article  PubMed  CAS  Google Scholar 

  12. Sasaki K, Yamano Y, Bardhan S, et al.: Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. Nature 1991, 351:230–233.

    Article  PubMed  CAS  Google Scholar 

  13. Burson JM, Aguilera G, Gross KW, Sigmund CD: Differential expression of angiotensin receptor 1A and 1B in mouse. Am J Physiol 1994, 267:E260–E267.

    PubMed  CAS  Google Scholar 

  14. Aguilera G: Role of angiotensin II receptor subtypes on the regulation of aldosterone secretion in the adrenal glomerulosa zone in the rat. Mol Cell Endocrinol 1992, 90:53–60.

    Article  PubMed  CAS  Google Scholar 

  15. Masilamani S, Kim GH, Mitchell C, et al.: Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest 1999, 104:R19–R23.

    Article  PubMed  CAS  Google Scholar 

  16. Morris MJ, Wilson WL, Starbuck EM, Fitts DA: Forebrain circumventricular organs mediate salt appetite induced by intravenous angiotensin II in rats. Brain Res 2002, 949:42–50.

    Article  PubMed  CAS  Google Scholar 

  17. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD: Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest 2000, 106:103–106.

    Article  PubMed  CAS  Google Scholar 

  18. Ichikawa I, Brenner BM: Importance of efferent arteriolar vascular tone in regulation of proximal tubule fluid reab-sorption and glomerulotubular balance in the rat. J Clin Invest 1980, 65:1192–1201.

    Article  PubMed  CAS  Google Scholar 

  19. Navar LG, Carmines PK, Huang WC, Mitchell KD: The tubular effects of angiotensin II. Kidney Int Suppl 1987, 20:S81–S88.

    PubMed  CAS  Google Scholar 

  20. Cogan MG: Angiotensin II: a powerful controller of sodium transport in the early proximal tubule. Hypertension 1990, 15:451–458.

    PubMed  CAS  Google Scholar 

  21. Bell PD, Peti-Peterdi J: Angiotensin II stimulates macula densa basolateral sodium/hydrogen exchange via type 1 angiotensin II receptors. J Am Soc Nephrol 1999, 10(Suppl 11):S225–S229.

    PubMed  CAS  Google Scholar 

  22. Peti-Peterdi J, Warnock DG, Bell PD: Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT(1) receptors. J Am Soc Nephrol 2002, 13:1131–1135.

    Article  PubMed  CAS  Google Scholar 

  23. Hall JE: Control of sodium excretion by angiotensin IId: intrarenal mechanisms and blood pressure regulation. Am J Physiol 1986, 250:R960–R972.

    PubMed  CAS  Google Scholar 

  24. Brenner BM, Cooper ME, de Zeeuw D, et al.: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001, 345:861–869.

    Article  PubMed  CAS  Google Scholar 

  25. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group [no authors listed]. N Engl J Med 1987, 316:1429–1435.

  26. Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001, 345:1667–1675.

    Article  PubMed  CAS  Google Scholar 

  27. Oliverio MI, Best CF, Smithies O, Coffman TM: Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin II. Hypertension 2000, 35:550–554.

    PubMed  CAS  Google Scholar 

  28. Crowley SD, Gurley SB, Oliverio MI, et al.: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005, 115:1092–1099.

    PubMed  CAS  Google Scholar 

  29. Brenner R, Perez GJ, Bonev AD, et al.: Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 2000, 407:870–876.

    Article  PubMed  CAS  Google Scholar 

  30. Zhu Y, Bian Z, Lu P, et al.: Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002, 295:505–508.

    Article  PubMed  CAS  Google Scholar 

  31. Francois H, Athirakul K, Mao L, et al.: Role for thromboxane receptors in angiotensin-II-induced hypertension. Hypertension 2004, 43:364–369.

    Article  PubMed  CAS  Google Scholar 

  32. Vecchione C, Patrucco E, Marino G, et al.: Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med 2005, 201:1217–1228.

    Article  PubMed  CAS  Google Scholar 

  33. Crowley SD, Gurley SB, Herrera MJ, et al.: Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A 2006, 103:17985–17990.

    Article  PubMed  CAS  Google Scholar 

  34. Guyton AC, Coleman TG, Cowley AV Jr, et al.: Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med 1972, 52:584–594.

    Article  PubMed  CAS  Google Scholar 

  35. Koren MJ, Devereux RB, Casale PN, et al.: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991, 114:345–352.

    PubMed  CAS  Google Scholar 

  36. Levy D, Garrison RJ, Savage DD, et al.: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990, 322:1561–1566.

    PubMed  CAS  Google Scholar 

  37. Sadoshima J, Xu Y, Slayter HS, Izumo S: Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993, 75:977–984.

    Article  PubMed  CAS  Google Scholar 

  38. Schmieder RE, Martus P, Klingbeil A: Reversal of left ventricular hypertrophy in essential hypertension. A metaanalysis of randomized double-blind studies. JAMA 1996, 275:1507–1513.

    Article  PubMed  CAS  Google Scholar 

  39. Mathew J, Sleight P, Lonn E, et al.: Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001, 104:1615–1621.

    Article  PubMed  CAS  Google Scholar 

  40. Devereux RB, Dahlof B, Gerdts E, et al.: Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation 2004, 110:1456–1462.

    Article  PubMed  CAS  Google Scholar 

  41. Paradis P, Dali-Youcef N, Paradis FW, et al.: Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A 2000, 97:931–936.

    Article  PubMed  CAS  Google Scholar 

  42. Hein L, Stevens ME, Barsh GS, et al.: Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc Natl Acad Sci U S A 1997, 94:6391–6396.

    Article  PubMed  CAS  Google Scholar 

  43. Zhai P, Yamamoto M, Galeotti J, et al.: Cardiac-specific overexpression of AT1 receptor mutant lacking G{alpha}q/G{alpha}i coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest 2005, 115:3045–3056.

    Article  PubMed  CAS  Google Scholar 

  44. Lee RT, Bloch KD, Pfeffer JM, et al.: Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy. J Clin Invest 1988, 81:431–434.

    Article  PubMed  CAS  Google Scholar 

  45. Nakagawa O, Ogawa Y, Itoh H, et al.: Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an “emergency” cardiac hormone against ventricular overload. J Clin Invest 1995, 96:1280–1287.

    Article  PubMed  CAS  Google Scholar 

  46. D’Angelo DD, Sakata Y, Lorenz JN, et al.: Transgenic Galpha q overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci U S A 1997, 94:8121–8126.

    Article  PubMed  CAS  Google Scholar 

  47. Harada K, Komuro I, Shiojima I, et al.: Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice. Circulation 1998, 97:1952–1959.

    PubMed  CAS  Google Scholar 

  48. van Kats JP, Methot D, Paradis P, et al.: Use of a biological peptide pump to study chronic peptide hormone action in transgenic mice. Direct and indirect effects of angiotensin II on the heart. J Biol Chem 2001, 276:44012–44017.

    Article  PubMed  Google Scholar 

  49. Griffin KA, Bidani AK: Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade. Clin J Am Soc Nephrol 2006, 1:1054–1065.

    Article  PubMed  Google Scholar 

  50. Svensson P, de Faire U, Sleight P, et al.: Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE substudy. Hypertension 2001, 38:E28–E32.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Steven D. Crowley.

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Crowley, S.D., Coffman, T.M. In hypertension, the kidney breaks your heart. Curr Cardiol Rep 10, 470–476 (2008). https://doi.org/10.1007/s11886-008-0074-5

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