This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 48/1/141    most recent 01.HYP.0000229648.67883.f9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mogi, M. Articles by Horiuchi, M. Search for Related Content PubMed PubMed Citation Articles by Mogi, M. Articles by Horiuchi, M. Related Collections ACE/Angiotension receptors Cerebrovascular disease/stroke Acute Cerebral Infarction Behavioral Changes and Stroke Neuroprotectors Other Stroke Treatment - Medical

(Hypertension. 2006;48:141.)
© 2006 American Heart Association, Inc.

Original Articles

Angiotensin II Type-2 Receptor Stimulation Prevents Neural Damage by Transcriptional Activation of Methyl Methanesulfonate Sensitive 2

Masaki Mogi; Jian-Mei Li; Jun Iwanami; Li-Juan Min; Kana Tsukuda; Masaru Iwai; Masatsugu Horiuchi

From the Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

The molecular mechanisms of the contribution of angiotensin II type-1 receptor blockers to neuronal protection are still unclear. Here, we investigated the effect of angiotensin II type-2 (AT₂) receptor stimulation on neurons and cognitive function involving a new neuroprotective factor, methyl methanesulfonate sensitive 2 (MMS2). Angiotensin II treatment of neurospheres enhanced their differentiation and increased MMS2 expression. Knockdown of the MMS2 gene by small interference RNA (siRNA) significantly reduced the number of neurospheres, with loss of sphere formation. An angiotensin II type-1 receptor blocker, valsartan, enhanced such neurosphere differentiation and MMS2 induction, whereas an AT₂ receptor antagonist, PD123319, inhibited them. After mice underwent permanent middle cerebral artery occlusion, AT₂ receptor mRNA expression was significantly increased in the ischemic side of the brain. Passive avoidance rate to evaluate cognitive function was significantly impaired in AT₂ receptor null (Agtr2–) mice compared with wild-type mice. Treatment with valsartan prevented the cognitive decline in wild-type mice, but this effect was weaker in Agtr2– mice. In ischemic brain regions, MMS2 was increased in wild-type mice, but not in Agtr2– mice. Valsartan also enhanced MMS2 expression to a greater degree in wild-type mice. Finally, intracerebroventricular administration of MMS2 siRNA showed more impaired avoidance rate after middle cerebral artery occlusion compared with that in control siRNA–transfected mice. These findings experimentally support the clinical evidence and indicate a unique mechanism of the AT₂ receptor in brain protection.

Key Words: stroke • angiotensin II • receptors angiotensin II • antihypertensive agents • central nervous system • neuroregulators

This article has been cited by other articles:

				C. A. McCarthy, A. Vinh, J. K. Callaway, and R. E. Widdop Angiotensin AT2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke * Supplemental Materials and Methods Stroke, April 1, 2009; 40(4): 1482 - 1489. [Abstract] [Full Text] [PDF]

				M Kawajiri, M Mogi, N Higaki, T Matsuoka, Y Ohyagi, K Tsukuda, K Kohara, M Horiuchi, T Miki, and J. Kira Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis Multiple Sclerosis, February 1, 2009; 15(2): 262 - 265. [Abstract] [PDF]

				S. Inaba, M. Iwai, Y. Tomono, I. Senba, M. Furuno, H. Kanno, H. Okayama, M. Mogi, J. Higaki, and M. Horiuchi Exaggeration of Focal Cerebral Ischemia in Transgenic Mice Carrying Human Renin and Human Angiotensinogen Genes Stroke, February 1, 2009; 40(2): 597 - 603. [Abstract] [Full Text] [PDF]

				S. Inaba, M. Iwai, M. Furuno, Y. Tomono, H. Kanno, I. Senba, H. Okayama, M. Mogi, J. Higaki, and M. Horiuchi Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice Hypertension, February 1, 2009; 53(2): 356 - 362. [Abstract] [Full Text] [PDF]

				J. Iwanami, M. Mogi, J.-M. Li, K. Tsukuda, L.-J. Min, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Deletion of Angiotensin II Type 2 Receptor Attenuates Protective Effects of Bone Marrow Stromal Cell Treatment on Ischemia-Reperfusion Brain Injury in Mice * Supplemental Materials and Methods Stroke, September 1, 2008; 39(9): 2554 - 2559. [Abstract] [Full Text] [PDF]

				J.-M. Li, M. Mogi, J. Iwanami, L.-J. Min, K. Tsukuda, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Temporary Pretreatment With the Angiotensin II Type 1 Receptor Blocker, Valsartan, Prevents Ischemic Brain Damage Through an Increase in Capillary Density Stroke, July 1, 2008; 39(7): 2029 - 2036. [Abstract] [Full Text] [PDF]

				M Kawajiri, M Mogi, M Osoegawa, T Matsuoka, K Tsukuda, K Kohara, M Horiuchi, T Miki, and J. Kira Reduction of angiotensin II in the cerebrospinal fluid of patients with multiple sclerosis Multiple Sclerosis, May 1, 2008; 14(4): 557 - 560. [Abstract] [PDF]

				L.-J. Min, M. Mogi, J. Iwanami, J.-M. Li, A. Sakata, T. Fujita, K. Tsukuda, M. Iwai, and M. Horiuchi Angiotensin II Type 2 Receptor Deletion Enhances Vascular Senescence by Methyl Methanesulfonate Sensitive 2 Inhibition Hypertension, May 1, 2008; 51(5): 1339 - 1344. [Abstract] [Full Text] [PDF]

				K. Tsukuda, M. Mogi, J.-M. Li, J. Iwanami, L.-J. Min, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Diabetes-Associated Cognitive Impairment Is Improved by a Calcium Channel Blocker, Nifedipine Hypertension, February 1, 2008; 51(2): 528 - 533. [Abstract] [Full Text] [PDF]

				M. Mogi, M. Iwai, and M. Horiuchi Emerging Concepts of Regulation of Angiotensin II Receptors: New Players and Targets for Traditional Receptors Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2532 - 2539. [Abstract] [Full Text] [PDF]

				K. Tsukuda, M. Mogi, J.-M. Li, J. Iwanami, L.-J. Min, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Amelioration of Cognitive Impairment in the Type-2 Diabetic Mouse by the Angiotensin II Type-1 Receptor Blocker Candesartan Hypertension, December 1, 2007; 50(6): 1099 - 1105. [Abstract] [Full Text] [PDF]

				M. Mogi, M. Iwai, and M. Horiuchi Emerging Concept of Adipogenesis Regulation by the Renin-Angiotensin System Hypertension, December 1, 2006; 48(6): 1020 - 1022. [Full Text] [PDF]