THE ROLE OF ANGIOTENSIN II TYPE 2 RECEPTORS (AT2RS) IN THE REGULATION OF CARDIO-RENAL AND NEUROPROTECTIVE ACTIVITIES: POTENTIAL THERAPEUTIC IMPLICATIONS
Abstract
Most of the physiological effects of the rennin-angiotensin system (RAS) are mediated by angiotensin II (AgII) type one receptors (AT1R), producing cellular dedifferentiation and proliferation; vasoconstriction; renal tubule sodium (Na+) reabsorption etc. However, the pathophysiologic role of AgII type two receptor (AT2R) has not been clearly defined yet. This review was, therefore, aimed at summarizing a plenty of primary literatures related to the role of AT2R. AT2R is a special G protein coupled receptor that is not coupled with the usual second messengers. The expression level of AT2R is greater in the neonates and fetal ages than in adults though its expression is up-regulated following tissue injury in adults implicating its role in regulating cell differentiation, growth and inflammations. Most of the cellular actions mediated by AT2R are counter regulatory to that of AT1R. AgII produces the cellular effects by acting on AT2R via different signal transduction pathways. The common cellular effects mediated by AT2R are antiproliferative, anti-inflammatory, vasodilation, natriuresis, etc which may be essential for modulating the cardiovascular, renal and brain injuries caused by different etiologies. The principal molecular signal transductions mediated by AT2R involve stimulation of the bradykinin and/or nitric oxide-cGMP pathwy, inactivation of mitogen activated protein kinase pathway by stimulating tyrosine and serine/threonien phosphatses, production of the neuroprotective factors, like BDNF, etc. These signaling pathways may exert cardio-renal and neuroprotective functions. Therefore, the development of drugs that stimulate the AT2R may the potential target to promote the treatment of different disorders related to the cardiovascular, renal and brain dysfunctions.
Keywords: Angiotensin II, AT2R, cardiovascular system, Renal system, neuroprotection
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Keywords:
Angiotensin II, AT2R, cardiovascular system, Renal system, neuroprotection
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References
1. Padia SH., Carey RM., AT2 receptors: Beneficial counter-regulatory role in cardiovascular and renal function. European Journal of Physiolog 2013; 465: 99–110.
2. Wright JW., Kawas LH., Harding JW., A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Frontiers in endocrinology 2013; 3:158.
3. De Gasparo M., Catt KJ., Inagami T., Wright JW, Unger T., International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacology Review 2000; 52:415–472.
4. Steckelings UM., Rompe F., Kaschina E., Namsolleck P., Grzesiak A., Funke-Kaiser H., et al.,The past, present and future of angiotensin II type 2 receptor stimulation. Journal of Renin-Angiotensin-Aldosterone System 2010; 11:67–73.
5. Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S, et al., Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression. Circulation Research 1998; 83: 1035-1046.
6. Yu L., Zheng M., Wang W., Rozanski GJ., Zucker IH, Gao L., Developmental changes in AT1 and AT2 receptor-protein expression in rats. Journal of Renin Angiotensin Aldosterone System 2011; 11: 214–221.
7. Zhang J., Pratt RE., The AT2 Receptor Selectively Associates with Giα2 and Giα3 in the Rat Fetus. The Journal of Biological Chemistry 2010; 271: 15026–15033.
8. Mukoyama M., Nakajima M., Horiuchi M., Sasamura H., Pratt RE., Dzau VJ., Expression Cloning of Type 2 Angiotensin II Receptor Reveals a Unique Class of Seven-transmembrane Receptors. The Journal of Biological Chemistry 1993; 268: 24539-24542.
9. Miuraa S., Matsuoa Y., Kiyaa Y., Karnikb SS., Sakua K.., Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors. Biochemical and Biophysical Research Communications 2010; 391: 85–90.
10. Carey RM, Wang Z, Siragy HM. Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function. Hypertension 2000, 35:155-163
11. Bosnyak S, Welungoda IK, Hallberg A, Alterman M, Widdop RE, Jones ES. Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. British Journal of Pharmacology 2010, 159: 709–716
12. Barber MN, Sampey DB, Widdop RE. AT2 Receptor Stimulation Enhances Antihypertensive Effect of AT1 Receptor Antagonist in Hypertensive Rats. Hypertension 1999, 34: 1112-1116
13. Widdop RE, Matrougui K, Levy BI, Henrion D. AT2 Receptor-Mediated Relaxation is Preserved After Long-Term AT1 Receptor. Hypertension 2002, 40:516-520.
14. Pulgar VM, Yamashiro H, Rose JC, Moore LG. Role of the AT2 receptor in modulating the angiotensin-II contractile response of the uterine artery at mid gestation. Journal of Renin Angiotensin Aldosterone System 2011, 12: 176–183.
15. Hannan RE, Davis EA, Widdop RE. Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide. British Journal of Pharmacology 2003, 140: 987–995.
16. Katada J, and Majima M . AT2 receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions. British Journal of Pharmacolog 2002, 136: 484-491
17. Gao L, Zucker IH. AT2 receptor signaling and sympathetic regulation. Current Opinion Pharmacology 2011, 11:124-130.
18. Li Y, Li X, Yuan H. Angiotensin II type-2 receptor-specific effects on the cardiovascular system. Cardiovascular Diagnosis and Therapy 2012, 2: 56-62.
19. Kats JP, Duncker DJ, Haitsma DB, Schuijt MP, Niebuur R, Stubenitsky R, et al. Angiotensin- converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling 2000
20. Brede M, Roell W, Ritter O, Wiesmann F, Jahns R, Haase A, et al. Cardiac Hypertrophy Is Associated with Decreased eNOS Expression in Angiotensin AT2 Receptor–Deficient Mice. Hypertension 2003, 42: 1177-1182.
21. Metcalfe BL, Huentelman MJ, Parilak LD, Taylor DG, Katovich MJ, Knot HJ, et al . Prevention of Cardiac Hypertrophy by Angiotensin II Type-2 Receptor Gene Transfer. Hypertension 2004, 43:1233-1238
22. Lakó-Futó Z, Szokodi I, Sármán B, Földes G, Tokola H, Ilves M, et al. Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac hypertrophic Process in Vivo in the Rat Heart. Circulation 2003, 108: 2414-2422.
23. Ichihara S, Senbonmatsu T, Jr EP, Ichiki T, Gaffney FA, Inagami T. Angiotensin II Type 2 Receptor: Is Essential for Left Ventricular Hypertrophy and Cardiac Fibrosis in Chronic Angiotensin II -Induced Hypertension. Circulation 2001, 104: 346-35.
24. Jehle AB, Xu Y, DiMaria JM, French BA, Epstein FH, Berr SS, et al. A Non-peptide Angiotensin II Type 2 Receptor Agonist Does Not Attenuate Post-Myocardial Infarction Left Ventricular Remodeling in Mice. Journal of Cardiovascular Pharmacology 2012, 59: 363–368.
25. Jalowy A, Schulz R, Do¨rge H, Behrends M, Heusch G. Infarct Size Reduction by AT1-Receptor Blockade Through a Signal Cascade of AT2-Receptor Activation, Bradykinin and Prostaglandins in Pigs. Journal of American College of Cardiology 1998, 32:1787–96.
26. Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, et al. Angiotensin II Type 2 Receptor Stimulation: A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction? Circulation 2008, 118: 2523-2532.
27. Yang Z, Bove CM, French BA, Epstein FH, Berr SS, DiMaria JM, et al . Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction. Circulation 2002, 106:106-111.
28. Adachi,Y, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N, et al. Angiotensin II Type 2 Receptor Deficiency Exacerbates Heart Failure and Reduces Survival after Acute Myocardial Infarction in Mice. Circulation 2003, 107: 2406-2408.
29. Oishi Y, Ozono R, Yano Y, Teranishi Y, Akishita M, Horiuchi M, et al. Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling. Hypertension 2003, 41: 814-818.
30. Miyata N, Park F, Li XF, Cowley AW. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. American Journal of Physiology 1999, 277: F437–F446.
31. Wehbi GJ, Zimpelmann J, Carey RM., Levine DZ., Burns KD. Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. American Journal of Physiology 2001, 280: F254–F265.
32. Gimonet V, Bussieres L, Medjebeur AA, Gasser B, Lelongt B, Laborde K.. Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb. American Journal of Physiology 1998, 274: F1062–F1069.
33. Wolf G. Angiotensin II and tubular development. Nephrology Dialysis Transplantation 2002, 17: 48–51.
34. Maric C, Aldred GP, Harrris PJ, Alcorn D. Angiotensin II inhibits the growth of cultured embryonic renomedullary interstitial cells through AT2R. Kidney international 1998, 53:92-99.
35. Gross V, Schunck W, Honeck H, Milia AF, Rgel EK, Walther T, et al. Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Kidney International 2000, 57:191–202.
36. 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. Proceeding national academy for science 1999, 96: 6506–6510.
37. Hakam AC, Siddiqui AH, Hussain T. Renal angiotensin II AT2 receptors promote natriuresis in streptozotocin-induced diabetic rats. American Journal of Physiology- Renal Physiology 2006, 290: F503–F508.
38. Ali Q and Hussain T. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats. Hypertension Research 2012, 35: 654–660.
39. Sabuhi R, Ali Q, Asghar M, Al-Zamily NRH, Hussain T. Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats. American Journal of Physiology- Renal Physiology 2011, 300: F700–F706.
40. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney international 1998, 53: 937-944.
41. Morrissey JJ, Klah S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. American journal of physiology 1999, 276: F39–F45.
42. Dhande I, Ali Q, Hussain T. Proximal tubule angiotensin at2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats. Hypertension 2013, 61: 1218–1226.
43. Matsubara H. Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases. Circulation research 1998, 83: 1182-1191.
44. Millan MA, Jacobowitz DM, Aguilera G, Catt KJ. Differential distribution of AT1 and AT2 angiotensin II receptor subtypes in the rat brain during development. Proceeding National Academy for Science 1991, 88: 11440-11444.
45. Coleman CG, Anrather, J, Iadecola C, Pickel VM. Angiotensin II type 2 (AT2) receptors have a major somatodendritic distribution in vasopressin-containing neurons in the mouse hypothalamic paraventricular nucleus. Neuroscience 2009, 163: 129–142.
46. Han NL, Sim MK. Hypothalamic angiotensin receptor subtypes in normotensive and hypertensive rats. American Journal of Physiology 1998, 275: H703–H709.
47. Anand U, Facer P, Yiangou Y., Sinisi M, Fox M, McCarthy T, et al. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. European Journal of Pain 2013, 17: 1012–1026.
48. Sumners C, Tang W, Zelezna B, Raizada MK.. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain. Proceeding National Academy for Science 1991, 88:7567-7571.
49. Gendron L, Payet, MD, Gallo-Payet N. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. Journal of Molecular Endocrinology 1991, 31, 359–372.
50. Coˆ te´ F, Do TH, Laflamme L, Galloi J, Gallo-Payet N. Activation of the AT2 Receptor of Angiotensin II Induces Neurite Outgrowth and Cell Migration in Microexplant Cultures of the Cerebellum. The journal of biological chemistry 1999, 274: 31686–31692.
51. Anand U, Facer P, Yiangou Y., Sinisi M, Fox M, McCarthy T, et al. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. European Journal of Pain 2013, 17: 1012–1026.
52. Iwai M, Liu H, Chen R, Ide A, Okamoto S, Hata R, et al. Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation. Circulation 2004, 110: 843-848.
53. McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke. Stroke 2009, 40: 1482-1489
54. McCarthy CA, Vinh A, Miller AA, Hallberg A, Alterman M, Callaway JK, et al. Direct Angiotensin AT2 Receptor Stimulation Using a Novel AT2 Receptor Agonist, Compound 21, Evokes neuroprotection in Conscious Hypertensive Rats. Public library of science 2014, 9: e95762.
55. Tang M, Zhao L, Chen Y, Wang L, Zhang X. Angiotensin II protects cortical neurons against oxygen glucose deprivation induced injury in vitro. Biomedical reports 2014, 2: 112-116.
56. Mogi M, Li J, Iwanami J, Min L, Tsukuda K, Iwai M, et al. Angiotensin II Type-2 Receptor Stimulation Prevents Neural Damage by Transcriptional Activation of Methyl Methanesulfonate Sensitive 2. Hypertension 2006, 48: 141-148
57. Alhusban A, Kozak A, Ergul A, Fagan SC. AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator. Journal of Pharmacology and Experimental Therapeutics,2013
58. Abdalla S, Lother H, Missiry A, Langer A, Sergeev P, Faramawy Y, et al. Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease. Journal of Biological Chemistry 2009, 284: 6554-6565.
2. Wright JW., Kawas LH., Harding JW., A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Frontiers in endocrinology 2013; 3:158.
3. De Gasparo M., Catt KJ., Inagami T., Wright JW, Unger T., International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacology Review 2000; 52:415–472.
4. Steckelings UM., Rompe F., Kaschina E., Namsolleck P., Grzesiak A., Funke-Kaiser H., et al.,The past, present and future of angiotensin II type 2 receptor stimulation. Journal of Renin-Angiotensin-Aldosterone System 2010; 11:67–73.
5. Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S, et al., Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression. Circulation Research 1998; 83: 1035-1046.
6. Yu L., Zheng M., Wang W., Rozanski GJ., Zucker IH, Gao L., Developmental changes in AT1 and AT2 receptor-protein expression in rats. Journal of Renin Angiotensin Aldosterone System 2011; 11: 214–221.
7. Zhang J., Pratt RE., The AT2 Receptor Selectively Associates with Giα2 and Giα3 in the Rat Fetus. The Journal of Biological Chemistry 2010; 271: 15026–15033.
8. Mukoyama M., Nakajima M., Horiuchi M., Sasamura H., Pratt RE., Dzau VJ., Expression Cloning of Type 2 Angiotensin II Receptor Reveals a Unique Class of Seven-transmembrane Receptors. The Journal of Biological Chemistry 1993; 268: 24539-24542.
9. Miuraa S., Matsuoa Y., Kiyaa Y., Karnikb SS., Sakua K.., Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors. Biochemical and Biophysical Research Communications 2010; 391: 85–90.
10. Carey RM, Wang Z, Siragy HM. Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function. Hypertension 2000, 35:155-163
11. Bosnyak S, Welungoda IK, Hallberg A, Alterman M, Widdop RE, Jones ES. Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. British Journal of Pharmacology 2010, 159: 709–716
12. Barber MN, Sampey DB, Widdop RE. AT2 Receptor Stimulation Enhances Antihypertensive Effect of AT1 Receptor Antagonist in Hypertensive Rats. Hypertension 1999, 34: 1112-1116
13. Widdop RE, Matrougui K, Levy BI, Henrion D. AT2 Receptor-Mediated Relaxation is Preserved After Long-Term AT1 Receptor. Hypertension 2002, 40:516-520.
14. Pulgar VM, Yamashiro H, Rose JC, Moore LG. Role of the AT2 receptor in modulating the angiotensin-II contractile response of the uterine artery at mid gestation. Journal of Renin Angiotensin Aldosterone System 2011, 12: 176–183.
15. Hannan RE, Davis EA, Widdop RE. Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide. British Journal of Pharmacology 2003, 140: 987–995.
16. Katada J, and Majima M . AT2 receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions. British Journal of Pharmacolog 2002, 136: 484-491
17. Gao L, Zucker IH. AT2 receptor signaling and sympathetic regulation. Current Opinion Pharmacology 2011, 11:124-130.
18. Li Y, Li X, Yuan H. Angiotensin II type-2 receptor-specific effects on the cardiovascular system. Cardiovascular Diagnosis and Therapy 2012, 2: 56-62.
19. Kats JP, Duncker DJ, Haitsma DB, Schuijt MP, Niebuur R, Stubenitsky R, et al. Angiotensin- converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling 2000
20. Brede M, Roell W, Ritter O, Wiesmann F, Jahns R, Haase A, et al. Cardiac Hypertrophy Is Associated with Decreased eNOS Expression in Angiotensin AT2 Receptor–Deficient Mice. Hypertension 2003, 42: 1177-1182.
21. Metcalfe BL, Huentelman MJ, Parilak LD, Taylor DG, Katovich MJ, Knot HJ, et al . Prevention of Cardiac Hypertrophy by Angiotensin II Type-2 Receptor Gene Transfer. Hypertension 2004, 43:1233-1238
22. Lakó-Futó Z, Szokodi I, Sármán B, Földes G, Tokola H, Ilves M, et al. Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac hypertrophic Process in Vivo in the Rat Heart. Circulation 2003, 108: 2414-2422.
23. Ichihara S, Senbonmatsu T, Jr EP, Ichiki T, Gaffney FA, Inagami T. Angiotensin II Type 2 Receptor: Is Essential for Left Ventricular Hypertrophy and Cardiac Fibrosis in Chronic Angiotensin II -Induced Hypertension. Circulation 2001, 104: 346-35.
24. Jehle AB, Xu Y, DiMaria JM, French BA, Epstein FH, Berr SS, et al. A Non-peptide Angiotensin II Type 2 Receptor Agonist Does Not Attenuate Post-Myocardial Infarction Left Ventricular Remodeling in Mice. Journal of Cardiovascular Pharmacology 2012, 59: 363–368.
25. Jalowy A, Schulz R, Do¨rge H, Behrends M, Heusch G. Infarct Size Reduction by AT1-Receptor Blockade Through a Signal Cascade of AT2-Receptor Activation, Bradykinin and Prostaglandins in Pigs. Journal of American College of Cardiology 1998, 32:1787–96.
26. Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, et al. Angiotensin II Type 2 Receptor Stimulation: A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction? Circulation 2008, 118: 2523-2532.
27. Yang Z, Bove CM, French BA, Epstein FH, Berr SS, DiMaria JM, et al . Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction. Circulation 2002, 106:106-111.
28. Adachi,Y, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N, et al. Angiotensin II Type 2 Receptor Deficiency Exacerbates Heart Failure and Reduces Survival after Acute Myocardial Infarction in Mice. Circulation 2003, 107: 2406-2408.
29. Oishi Y, Ozono R, Yano Y, Teranishi Y, Akishita M, Horiuchi M, et al. Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling. Hypertension 2003, 41: 814-818.
30. Miyata N, Park F, Li XF, Cowley AW. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. American Journal of Physiology 1999, 277: F437–F446.
31. Wehbi GJ, Zimpelmann J, Carey RM., Levine DZ., Burns KD. Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. American Journal of Physiology 2001, 280: F254–F265.
32. Gimonet V, Bussieres L, Medjebeur AA, Gasser B, Lelongt B, Laborde K.. Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb. American Journal of Physiology 1998, 274: F1062–F1069.
33. Wolf G. Angiotensin II and tubular development. Nephrology Dialysis Transplantation 2002, 17: 48–51.
34. Maric C, Aldred GP, Harrris PJ, Alcorn D. Angiotensin II inhibits the growth of cultured embryonic renomedullary interstitial cells through AT2R. Kidney international 1998, 53:92-99.
35. Gross V, Schunck W, Honeck H, Milia AF, Rgel EK, Walther T, et al. Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Kidney International 2000, 57:191–202.
36. 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. Proceeding national academy for science 1999, 96: 6506–6510.
37. Hakam AC, Siddiqui AH, Hussain T. Renal angiotensin II AT2 receptors promote natriuresis in streptozotocin-induced diabetic rats. American Journal of Physiology- Renal Physiology 2006, 290: F503–F508.
38. Ali Q and Hussain T. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats. Hypertension Research 2012, 35: 654–660.
39. Sabuhi R, Ali Q, Asghar M, Al-Zamily NRH, Hussain T. Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats. American Journal of Physiology- Renal Physiology 2011, 300: F700–F706.
40. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney international 1998, 53: 937-944.
41. Morrissey JJ, Klah S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. American journal of physiology 1999, 276: F39–F45.
42. Dhande I, Ali Q, Hussain T. Proximal tubule angiotensin at2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats. Hypertension 2013, 61: 1218–1226.
43. Matsubara H. Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases. Circulation research 1998, 83: 1182-1191.
44. Millan MA, Jacobowitz DM, Aguilera G, Catt KJ. Differential distribution of AT1 and AT2 angiotensin II receptor subtypes in the rat brain during development. Proceeding National Academy for Science 1991, 88: 11440-11444.
45. Coleman CG, Anrather, J, Iadecola C, Pickel VM. Angiotensin II type 2 (AT2) receptors have a major somatodendritic distribution in vasopressin-containing neurons in the mouse hypothalamic paraventricular nucleus. Neuroscience 2009, 163: 129–142.
46. Han NL, Sim MK. Hypothalamic angiotensin receptor subtypes in normotensive and hypertensive rats. American Journal of Physiology 1998, 275: H703–H709.
47. Anand U, Facer P, Yiangou Y., Sinisi M, Fox M, McCarthy T, et al. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. European Journal of Pain 2013, 17: 1012–1026.
48. Sumners C, Tang W, Zelezna B, Raizada MK.. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain. Proceeding National Academy for Science 1991, 88:7567-7571.
49. Gendron L, Payet, MD, Gallo-Payet N. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. Journal of Molecular Endocrinology 1991, 31, 359–372.
50. Coˆ te´ F, Do TH, Laflamme L, Galloi J, Gallo-Payet N. Activation of the AT2 Receptor of Angiotensin II Induces Neurite Outgrowth and Cell Migration in Microexplant Cultures of the Cerebellum. The journal of biological chemistry 1999, 274: 31686–31692.
51. Anand U, Facer P, Yiangou Y., Sinisi M, Fox M, McCarthy T, et al. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. European Journal of Pain 2013, 17: 1012–1026.
52. Iwai M, Liu H, Chen R, Ide A, Okamoto S, Hata R, et al. Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation. Circulation 2004, 110: 843-848.
53. McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke. Stroke 2009, 40: 1482-1489
54. McCarthy CA, Vinh A, Miller AA, Hallberg A, Alterman M, Callaway JK, et al. Direct Angiotensin AT2 Receptor Stimulation Using a Novel AT2 Receptor Agonist, Compound 21, Evokes neuroprotection in Conscious Hypertensive Rats. Public library of science 2014, 9: e95762.
55. Tang M, Zhao L, Chen Y, Wang L, Zhang X. Angiotensin II protects cortical neurons against oxygen glucose deprivation induced injury in vitro. Biomedical reports 2014, 2: 112-116.
56. Mogi M, Li J, Iwanami J, Min L, Tsukuda K, Iwai M, et al. Angiotensin II Type-2 Receptor Stimulation Prevents Neural Damage by Transcriptional Activation of Methyl Methanesulfonate Sensitive 2. Hypertension 2006, 48: 141-148
57. Alhusban A, Kozak A, Ergul A, Fagan SC. AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator. Journal of Pharmacology and Experimental Therapeutics,2013
58. Abdalla S, Lother H, Missiry A, Langer A, Sergeev P, Faramawy Y, et al. Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease. Journal of Biological Chemistry 2009, 284: 6554-6565.
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Molla Y, Sisay M. THE ROLE OF ANGIOTENSIN II TYPE 2 RECEPTORS (AT2RS) IN THE REGULATION OF CARDIO-RENAL AND NEUROPROTECTIVE ACTIVITIES: POTENTIAL THERAPEUTIC IMPLICATIONS. JDDT [Internet]. 15Mar.2017 [cited 19Apr.2024];7(2):110-8. Available from: https://jddtonline.info/index.php/jddt/article/view/1356
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