The "his and hers" of the renin-angiotensin system

Current Hypertension Reports

Volumn 15, Issue 1, 2013, Pages 71-79

  Hilliard, Lucinda M ^a   Sampson, Amanda K ^b   Brown, Russell D ^a   Denton, Kate M ^a  

^a MONASH UNIVERSITY   (Australia)

^b BAKER IDI HEART AND DIABETES INSTITUTE   (Australia)

Author keywords

Angiotensin (1 7); Angiotensin II; Angiotensin type 2 receptor; Angiotensin converting enzyme 2; Arterial blood pressure; Cardiovascular disease; Depressor arm of the RAS; Hypertension; Kidney function; Mas receptor; Sex chromosomes; Sex differences; Sex hormones

Indexed keywords

ANGIOTENSIN 1 RECEPTOR; ANGIOTENSIN II; DIPEPTIDYL CARBOXYPEPTIDASE; ESTROGEN; TESTOSTERONE;

ACE GENE; AGING; ARTICLE; AT1R GENE; BLOOD PRESSURE REGULATION; CARDIOVASCULAR DISEASE; GENE DELETION; GENE INSERTION; GENOTYPE; HEART PROTECTION; HETEROZYGOSITY; HOMOZYGOSITY; HORMONE ACTION; HUMAN; HYPERTENSION; KARYOTYPE 46,XX; KARYOTYPE 46,XY; KIDNEY DISEASE; KIDNEY FUNCTION; NONHUMAN; POSTMENOPAUSE; PREMENOPAUSE; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; SEX CHROMOSOME; SEX DIFFERENCE; SINGLE NUCLEOTIDE POLYMORPHISM; UPREGULATION;

ANIMALS; BLOOD PRESSURE; ESTROGENS; FEMALE; GENES, SRY; HUMANS; MALE; POLYMORPHISM, GENETIC; RECEPTORS, ANGIOTENSIN; RENIN; RENIN-ANGIOTENSIN SYSTEM; SEX CHROMOSOMES; SEX FACTORS; SIGNAL TRANSDUCTION; TESTOSTERONE;

EID: 84872597247     PISSN: 15226417     EISSN: 15343111     Source Type: Journal    
DOI: 10.1007/s11906-012-0319-y     Document Type: Article

References (95)

1. Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, Rabi D, Tremblay J, Alamian A, Barnett T, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ. 2007;176(6):S1-44.
2. Patlak M. His and her physiology and sex hormones. Endocr News. 2009;1(part 1):16-7.
3. Silbiger S, Neugarten J. Gender and human chronic renal disease. Gend Med. 2008;5(Suppl A):S3-10. (Pubitemid 351455227)
4. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res. 2007;55(2):81-95. (Pubitemid 46186037)
5. Zucker I, Beery AK. Males still dominate animal studies. Nature. 2010;465(7299):690.
6. Kang A, Miller J. Effects of gender on the renin-angiotensin system, blood pressure and renal function. Curr Hypertens Rep. 2002;4:143-51.
7. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension. 2001;37(5):1199-208. (Pubitemid 34163570)
8. Sandberg K, Ji H. Sex and the renin angiotensin system: implications for gender differences in the progression of kidney disease. Adv Ren Replace Ther. 2003;10(1):15-23. (Pubitemid 36278326)
9. Evans RG, Stevenson KM, Bergstrom G, Denton KM, Madden AC, Gribben RL, Weekes SR, Anderson WP. Sex differences in pressure diuresis/natriuresis in rabbits. Acta Physiol Scand. 2000;169(4):309-16.
10. Wiinberg N, Hoegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen TL, Kampmann JP, Madsen NH, Bentzon MW. 24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens. 1995;8(10 Pt 1):978-86.
11. Schrier RW, Ohara M. Dilemmas in human and rat pregnancy: proposed mechanisms relating to arterial vasodilation. J Neuroendocrinol. 2010;22(5):400-6.
12. Valdiviezo C, Garovic VD, Ouyang P. Preeclampsia and hypertensive disease in pregnancy: their contributions to cardiovascular risk. Clin Cardiol. 2012;35(3):160-5.
13. Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002;53:672-7. (Pubitemid 34175260)
14. Sullivan JC. Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. Am J Physiol Regul Integr Comp Physiol. 2008;294(4):R1220-6. (Pubitemid 351490641)
15. Xue B, Johnson AK, Hay M. Sex differences in angiotensin II- induced hypertension. Braz J Med Biol Res. 2007;40:727-34. (Pubitemid 46722220)
16. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin- aldosterone system. Fundam Clin Pharmacol. 2010;24(6):687-98.
17. Sampson AK, Widdop RE, Denton KM. Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats. Clin Exp Pharmacol Physiol. 2008;35(4):391-5. (Pubitemid 351326767)
18. Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther. 2008;120(3):292-316.
19. Schunkert H, Danser AH, Hense HW, Derkx FH, Kurzinger S, Riegger GA. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation. 1997;95(1):39-45. (Pubitemid 27029940)
20. Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra JM. Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul Pept. 2005;124(1-3):7-17. (Pubitemid 39488336)
21. Miyata N, Park F, Li XF, Cowley Jr AW. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am J Physiol. 1999;277(3 Pt 2):F437-46.
22. Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy HM, Carey RM. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension. 1997;30(5):1238-46. (Pubitemid 27476185)
23. Reckelhoff JF. Sex and sex steroids in cardiovascular-renal physiology and pathophysiology. Gend Med. 2008;5(Suppl A):S1-2. (Pubitemid 351455226)
24. Sandberg K, Ji H. Why can't a woman be more like a man?: Is the angiotensin type 2 receptor to blame or to thank? Hypertension. 2008;52(4):615-7.
25. 2 R in female but not male rats.
26. Sampson AK, Hilliard LM, Moritz KM, Thomas MC, Tikellis C, Widdop RE, Denton KM. The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent. Am J Physiol Regul Integr Comp Physiol. 2012;302(1):R159-65.
27. 2 R in males and females, such that in females, tubuloglomerular feedback sensitivity was not enhanced in response to subpressor AngII infusion, unlike the situation in males.
28. •• Liu J, Ji H, Zheng W, Wu X, Zhu JJ, Arnold AP, Sandberg K. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ. 2010;1(1):6. This studied showed that ACE2 activity was regulated by estrogen and that this contributed to the attenuated response to AngII infusion females as compared to males.
29. Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure-a population study. Eur J Heart Fail. 2007;9(6-7):602-9. (Pubitemid 46702819)
30. Os I, Franco V, Kjeldsen SE, Manhem K, Devereux RB, Gerdts E, Hille DA, Lyle PA, Okin PM, Dahlof B, et al. Effects of losartan in women with hypertension and left ventricular hypertrophy: results from the Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension. 2008;51(4):1103-8. (Pubitemid 351398965)
31. •• Hladunewich MA, Kingdom J, Odutayo A, Burns K, Lai V, O'Brien T, Gandhi S, Zimpelmann J, Kiss A, Miller J, et al. Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia. J Clin Endocrinol Metab. 2011;96(11):3517-24. This work highlighted the potential for loss of normal regulation of arterial pressure by the vasodepressor arm of the RAS in women might play a role in pre-eclampsia and increased risk of cardiovascular disease in later life.
32. Takeda-Matsubara Y, Iwai M, Cui TX, Shiuchi T, Liu HW, Okumura M, Ito M, Horiuchi M. Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change. Am J Hypertens. 2004;17(8):684-9. (Pubitemid 39091549)
33. Miller JA, Cherney DZ, Duncan JA, Lai V, Burns KD, Kennedy CR, Zimpelmann J, Gao W, Cattran DC, Scholey JW. Gender differences in the renal response to renin-angiotensin system blockade. J Am Soc Nephrol. 2006;17(9):2554-60. (Pubitemid 44300971)
34. Silbiger S. Renal hemodynamic responses to renin-angiotensin blockade differ in men and women. Nat Clin Pract. 2007;3(2):68-9. (Pubitemid 46160993)
35. Miller JA, Anacta LA, Cattran DC. Impact of gender on the renal response to angiotensin II. Kidney Int. 1999;55(1):278-85. (Pubitemid 29004260)
36. Chen YF, Meng QC. Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent. Life Sci. 1991;48(1):85-96.
37. Crofton JT, Ota M, Share L. Role of vasopressin, the renin-angiotensin system and sex in Dahl salt-sensitive hypertension. J Hypertens. 1993;11(10):1031-8. (Pubitemid 23307874)
38. Ganten U, Schroder G, Witt M, Zimmermann F, Ganten D, Stock G. Sexual dimorphism of blood pressure in spontaneously hypertensive rats: effects of anti-androgen treatment. J Hypertens. 1989;7(9):721-6. (Pubitemid 19230550)
39. Iams SG, Wexler BC. Retardation in the development of spontaneous hypertension in SH rats by gonadectomy. J Lab Clin Med. 1977;90(6):997-1003. (Pubitemid 8235973)
40. Malyusz M, Ehrens HJ, Wrigge P. Effect of castration on the experimental renal hypertension of the rat. Blood pressure, nephrosclerosis, long-chain fatty acids, and N-acetylation of PAH in the kidney. Nephron. 1985;40(1):96-9.
41. Masubuchi Y, Kumai T, Uematsu A, Komoriyama K, Hirai M. Gonadectomy-induced reduction of blood pressure in adult spontaneously hypertensive rats. Acta Endocrinol (Copenh). 1982;101(1):154-60. (Pubitemid 12043928)
42. Reckelhoff JF, Zhang H, Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension. 1998;31(1 Pt 2):435-9.
43. Rowland NE, Fregly MJ. Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin Exp Hypertens A. 1992;14(3):367-75.
44. Rettig R, Folberth CG, Stauss H, Kopf D, Waldherr R, Baldauf G, Unger T. Hypertension in rats induced by renal grafts from renovascular hypertensive donors. Hypertension. 1990;15(4):429-35. (Pubitemid 20137600)
45. Harrap SB, Wang BZ, MacLellan DG. Renal transplantation between male and female spontaneously hypertensive rats. Hypertension. 1992;19(5):431-4.
46. Chen YF, Naftilan AJ, Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension. 1992;19(5):456-63.
47. Ellison KE, Ingelfinger JR, Pivor M, Dzau VJ. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest. 1989;83(6):1941-5. (Pubitemid 19148864)
48. Johnston CI, Fabris B, Jandeleit K. Intrarenal renin-angiotensin system in renal physiology and pathophysiology. Kidney Int Suppl. 1993;42:S59-63.
49. Katz FH, Roper EF. Testosterone effect on renin system in rats. Proc Soc Exp Biol Med. 1977;155(3):330-3. (Pubitemid 8168674)
50. Kienitz T, Quinkler M. Testosterone and blood pressure regulation. Kidney Blood Press Res. 2008;31(2):71-9. (Pubitemid 351630063)
51. Reckelhoff JF, Zhang H, Srivastava K, Granger JP. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. Hypertension. 1999;34(4 Pt 2):920-3. (Pubitemid 29501324)
52. Quan A, Chakravarty S, Chen JK, Chen JC, Loleh S, Saini N, Harris RC, Capdevila J, Quigley R. Androgens augment proximal tubule transport. Am J Physiol Renal Physiol. 2004;287(3):F452-9. (Pubitemid 39095959)
53. Reckelhoff JF, Zhang H, Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system. Hypertension. 2000;35(1 Pt 2):480-3. (Pubitemid 30054220)
54. De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci. 2002;22(20):9005-14. (Pubitemid 35379070)
55. Ely DL, Turner ME. Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome. Hypertension. 1990;16(3):277-81. (Pubitemid 20313289)
56. Negrin CD, McBride MW, Carswell HV, Graham D, Carr FJ, Clark JS, Jeffs B, Anderson NH, Macrae IM, Dominiczak AF. Reciprocal consomic strains to evaluate y chromosome effects. Hypertension. 2001;37(2 Part 2):391-7. (Pubitemid 32198999)
57. • Sampson AK, Jennings GL, Chin-Dusting JP. Y are males so difficult to understand?: a case where «X» does not mark the spot. Hypertension. 2012;59(3):525-31. Recent comprehensive review examining the contribution of the Y chromosome to hypertension.
58. Ji H, Zheng W, Wu X, Liu J, Ecelbarger CM, Watkins R, Arnold AP, Sandberg K. Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension. 2010;55(5):1275-82.
59. Milsted A, Underwood AC, Dunmire J, DelPuerto HL, Martins AS, Ely DL, Turner ME. Regulation of multiple renin-angiotensin system genes by Sry. J Hypertens. 2010;28(1):59-64.
60. Ely D, Milsted A, Dunphy G, Boehme S, Dunmire J, Hart M, Toot J, Turner M. Delivery of sry1, but not sry2, to the kidney increases blood pressure and sns indices in normotensive wky rats. BMC Physiol. 2009;9:10.
61. O'Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer EJ, Myers RH, Levy D. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation. 1998;97(18):1766-72.
62. Reich H, Duncan JA, Weinstein J, Cattran DC, Scholey JW, Miller JA. Interactions between gender and the angiotensin type 1 receptor gene polymorphism. Kidney Int. 2003;63(4):1443-9. (Pubitemid 36350009)
63. Lu N, Yang Y, Wang Y, Liu Y, Fu G, Chen D, Dai H, Fan X, Hui R, Zheng Y. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects. Mol Biol Rep. 2012;39(6):6581-9.
64. Mohana VU, Swapna N, Surender RS, Vishnupriya S, Padma T. Gender-related association of AGT gene variants (M235T and T174M) with essential hypertension-a case-control study. Clin Exp Hypertens. 2012;34(1):38-44.
65. Jeunemaitre X, Gimenez-Roqueplo AP, Celerier J, Corvol P. Angiotensinogen variants and human hypertension. Curr Hypertens Rep. 1999;1(1):31-41.
66. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6. (Pubitemid 20370444)
67. Cherney DZ, Lai V, Miller JA, Scholey JW, Reich HN. The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans. Nephrol Dial Transplant. 2010;25(12):4093-6.
68. Campbell CY, Fang BF, Guo X, Peralta CA, Psaty BM, Rich SS, Young JH, Coresh J, Kramer HJ, Rotter JI, et al. Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the Multi-ethnic Study of Atherosclerosis. Am J Nephrol. 2010;32(2):156-62.
69. Hall JE, Brands MW, Henegar JR. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol. 1999;10 Suppl 12:S258-65.
70. Sampson AK, Moritz KM, Denton KM. Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats. Gender Med. 2012.
71. 2 R plays in the regulation of renal function in both the sexes, which is particularly significant in females.
72. Khraibi AA, Liang M, Berndt TJ. Role of gender on renal interstitial hydrostatic pressure and sodium excretion in rats. Am J Hypertens. 2001;14(9 Pt 1):893-6. (Pubitemid 32862589)
73. Siragy HM. The angiotensin II type 2 receptor and the kidney. J Renin Angiotensin Aldosterone Syst. 2010;11(1):33-6.
74. Silva-Antonialli MM, Tostes RC, Fernandes L, Fior-Chadi DR, Akamine EH, Carvalho MH, Fortes ZB, Nigro D. A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc Res. 2004;62(3):587-93. (Pubitemid 38648973)
75. Armando I, Jezova M, Juorio AV, Terron JA, Falcon-Neri A, Semino-Mora C, Imboden H, Saavedra JM. Estrogen upregulates renal angiotensin II AT(2) receptors. Am J Physiol Renal Physiol. 2002;283(5):F934-43.
76. Schneider MP, Wach PF, Durley MK, Pollock JS, Pollock DM. Sex differences in acute ANG II-mediated hemodynamic responses in mice. Am J Physiol Regul Integr Comp Physiol. 2010;299(3):R899-906.
77. •• Sullivan JC, Bhatia K, Yamamoto T, Elmarakby AA. Angiotensin (1-7) receptor antagonism equalizes angiotensin II-induced hypertension in male and female spontaneously hypertensive rats. Hypertension. 2010;56(4):658-66. An important study that comprehensively examined the contribution of Ang(1-7) to the response to AngII infusion in the SHR model, demonstrating enhanced effects in females.
78. Gross V, Schunck WH, Honeck H, Milia AF, Kargel E, Walther T, Bader M, Inagami T, Schneider W, Luft FC. Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Kidney Int. 2000;57(1):191-202. (Pubitemid 30227766)
79. Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA. 1999;96(11):6506-10. (Pubitemid 29256696)
80. 2 R stimulation, with Compound 21, reduced renal vascular tone significantly more in females than males.
81. 2 R in the female vasculature, this work needs to be extended to examine the role of this peptide in the sex-dependent regulation of renal hemodynamics.
82. Padia SH, Kemp BA, Howell NL, Siragy HM, Fournie-Zaluski MC, Roques BP, Carey RM. Intrarenal aminopeptidase N inhibition augments natriuretic responses to angiotensin III in angiotensin type 1 receptor-blocked rats. Hypertension. 2007;49(3):625-30.
83. Padia SH, Kemp BA, Howell NL, Gildea JJ, Keller SR, Carey RM. Intrarenal angiotensin III infusion induces natriuresis and angiotensin type 2 receptor translocation in Wistar-Kyoto but not in spontaneously hypertensive rats. Hypertension. 2009;53(2):338-43.
84. Padia SH, Kemp BA, Howell NL, Fournie-Zaluski MC, Roques BP, Carey RM. Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats. Hypertension. 2008;51(2):460-5. (Pubitemid 351156433)
85. Padia SH, Howell NL, Siragy HM, Carey RM. Renal angiotensin type 2 receptors mediate natriuresis via angiotensin III in the angiotensin II type 1 receptor-blocked rat. Hypertension. 2006;47(3):537-44. (Pubitemid 43843872)
86. Ferrario CM, Varagic J. The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am J Physiol Renal Physiol. 2010;298(6):F1297-305.
87. Pinheiro SV, Simoes ESAC. Angiotensin converting enzyme 2, angiotensin-(1-7), and receptor MAS axis in the kidney. Int J Hypertens. 2012;2012:414128.
88. Zimmerman D, Burns KD. Angiotensin-(1-7) in kidney disease: a review of the controversies. Clin Sci. 2012;123(6):333-46.
89. Pendergrass KD, Pirro NT, Westwood BM, Ferrario CM, Brosnihan KB, Chappell MC. Sex differences in circulating and renal angiotensins of hypertensive mRen(2). Lewis but not normotensive Lewis rats. Am J Physiol Heart Circ Physiol. 2008;295(1):H10-20.
90. •• Barroso LC, Silveira KD, Lima CX, Borges V, Bader M, Rachid M, Santos RA, Souza DG, Simoes ESAC, Teixeira MM. Renoprotective effects of AVE0991, a nonpeptide Mas receptor agonist, in experimental acute renal injury. Int J Hypertens. 2012;2012:808726. This study demonstrated that direct MasR stimulation has therapeutic potential in the treatment of renal disease. Future work needs to explore the possiblity that these actions may be enhanced in females.
91. Burgelova M, Vanourkova Z, Thumova M, Dvorak P, Opocensky M, Kramer HJ, Zelizko M, Maly J, Bader M, Cervenka L. Impairment of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas axis contributes to the acceleration of two-kidney, one-clip Goldblatt hypertension. J Hypertens. 2009;27(10):1988-2000.
92. Dharmani M, Mustafa MR, Achike FI, Sim MK. Effects of angiotensin 1-7 on the actions of angiotensin II in the renal and mesenteric vasculature of hypertensive and streptozotocin-induced diabetic rats. Eur J Pharmacol. 2007;561(1-3):144-50. (Pubitemid 46435855)
93. Sampaio WO, Nascimento AA, Santos RA. Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats. Am J Physiol Heart Circ Physiol. 2003;284(6):H1985-94.
94. Safari T, Nematbakhsh M, Hilliard LM, Evans RG, Denton KM. Sex differences in the renal vascular response to angiotensin II involves the Mas receptor. Acta physiologica (Oxford, England) 2012.
95. • Horiuchi M, Iwanami J, Mogi M. Regulation of angiotensin II receptors beyond the classical pathway. Clin Sci. 2012;123(4):193-203. An excellent review focusing upon recent advances in the understanding of angiotensin receptor-interacting proteins and AngII receptor-activating mechanisms.