Published Online
on February 24, 2003

A more recent version of this article appeared on April 1, 2003

This Article Full Text (PDF) All Versions of this Article: 107/12/1632    most recent 01.CIR.0000058200.90059.B1v1 Alert me when this article is cited Alert me if a correction is posted 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 Dechend, R. Articles by Luft, F. C. Search for Related Content PubMed PubMed Citation Articles by Dechend, R. Articles by Luft, F. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Risk Pregnancy

Submitted on October 9, 2002
Revised on December 20, 2002
Accepted on January 2, 2003

AT₁ Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase

Ralf Dechend MD, Christiane Viedt MD, Dominik N. Müller PhD, Bernhard Ugele PhD, Ralf P. Brandes MD, Gerd Wallukat PhD, Joon-Keun Park PhD, Jurgen Janke PhD, Peter Barta MD, Jurgen Theuer MD, Anette Fiebeler MD, Volker Homuth MD, Rainer Dietz MD, Hermann Haller MD, Jörg Kreuzer MD, and Friedrich C. Luft MD^*

From HELIOS Klinikum-Berlin, Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin (R.D., D.N.M., G.W., J.J., P.B., J.T., V.H., R.D., F.C.L.); the Department of Internal Medicine III, University of Heidelberg (C.V., J.K.); the Department of Nephrology, Hannover University Medical School, Hannover (J.-K.P., A.F., H.H.); the Department of Obstetrics and Gynecology, Ludwig-Maximillian University, Munich (B.U.); and Physiology, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany (R.P.B.).

^* To whom correspondence should be addressed. E-mail: luft{at}fvk-berlin.de.

Background--We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT₁-AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT₁-AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-B (NF-B) activation.

Methods and Results--We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT₁-AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT₁-AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT₁-AA lead to NF-B activation in VSMC and trophoblasts. AT₁-AA activated NF-B. Inhibitor-B (I-B) expression was reduced in response to AT₁-AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-B activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-B activation in response to Ang II and AT1-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-B was activated and I-B reduced in placentas from preeclamptic women.

Conclusions--NADPH oxidase is potentially an important source of ROS that may upregulate NF-B in preeclampsia. We suggest that AT₁-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.

Key words: receptors, AT₁ • pregnancy • angiotensin • oxygen • cells • antibodies

This article has been cited by other articles:

				L. Anton, D. C. Merrill, L. A. A. Neves, D. I. Diz, J. Corthorn, G. Valdes, K. Stovall, P. E. Gallagher, C. Moorefield, C. Gruver, et al. The Uterine Placental Bed Renin-Angiotensin System in Normal and Preeclamptic Pregnancy Endocrinology, September 1, 2009; 150(9): 4316 - 4325. [Abstract] [Full Text] [PDF]

				F. Herse, S. Verlohren, K. Wenzel, J. Pape, D. N. Muller, S. Modrow, G. Wallukat, F. C. Luft, C. W.G. Redman, and R. Dechend Prevalence of Agonistic Autoantibodies Against the Angiotensin II Type 1 Receptor and Soluble fms-Like Tyrosine Kinase 1 in a Gestational Age-Matched Case Study Hypertension, February 1, 2009; 53(2): 393 - 398. [Abstract] [Full Text] [PDF]

				B. LaMarca, G. Wallukat, M. Llinas, F. Herse, R. Dechend, and J. P. Granger Autoantibodies to the Angiotensin Type I Receptor in Response to Placental Ischemia and Tumor Necrosis Factor {alpha} in Pregnant Rats Hypertension, December 1, 2008; 52(6): 1168 - 1172. [Abstract] [Full Text] [PDF]

				L. Anton and K. B. Brosnihan Review: Systemic and uteroplacental renin--angiotensin system in normal and pre-eclamptic pregnancies Therapeutic Advances in Cardiovascular Disease, October 1, 2008; 2(5): 349 - 362. [Abstract] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, S. Abbasi, L. Xia, M.-C. Day, S. M. Ramin, A. Ahmed, R. E. Kellems, and Y. Xia Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling Hypertension, April 1, 2008; 51(4): 1010 - 1019. [Abstract] [Full Text] [PDF]

				D. S. Hoffmann, C. J. Weydert, E. Lazartigues, W. J. Kutschke, M. F. Kienzle, J. E. Leach, J. A. Sharma, R. V. Sharma, and R. L. Davisson Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in BPH/5 Mouse Model of Preeclampsia Hypertension, April 1, 2008; 51(4): 1058 - 1065. [Abstract] [Full Text] [PDF]

				L. Hering, F. Herse, S. Verlohren, J.-K. Park, M. Wellner, F. Qadri, R. Pijnenborg, A. C. Staff, B. Huppertz, D. N. Muller, et al. Trophoblasts Reduce the Vascular Smooth Muscle Cell Proatherogenic Response Hypertension, February 1, 2008; 51(2): 554 - 559. [Abstract] [Full Text] [PDF]

				Y. Xia, C. C. Zhou, S. M. Ramin, and R. E. Kellems Angiotensin Receptors, Autoimmunity, and Preeclampsia J. Immunol., September 15, 2007; 179(6): 3391 - 3395. [Abstract] [Full Text] [PDF]

				J. V. Ilekis, U. M. Reddy, and J. M. Roberts Review Article: Preeclampsia A Pressing Problem: An Executive Summary of a National Institute of Child Health and Human Development Workshop Reproductive Sciences, September 1, 2007; 14(6): 508 - 523. [Abstract] [PDF]

				A. Sachse and G. Wolf Angiotensin II Induced Reactive Oxygen Species and the Kidney J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2439 - 2446. [Abstract] [Full Text] [PDF]

				Y. Xia, S. M. Ramin, and R. E. Kellems Potential Roles of Angiotensin Receptor-Activating Autoantibody in the Pathophysiology of Preeclampsia Hypertension, August 1, 2007; 50(2): 269 - 275. [Full Text] [PDF]

				A. Tesse, F. Meziani, E. David, N. Carusio, H. Kremer, F. Schneider, and R. Andriantsitohaina Microparticles from preeclamptic women induce vascular hyporeactivity in vessels from pregnant mice through an overproduction of NO Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H520 - H525. [Abstract] [Full Text] [PDF]

				C. A. Hubel, G. Wallukat, M. Wolf, F. Herse, A. Rajakumar, J. M. Roberts, N. Markovic, R. Thadhani, F. C. Luft, and R. Dechend Agonistic Angiotensin II Type 1 Receptor Autoantibodies in Postpartum Women With a History of Preeclampsia Hypertension, March 1, 2007; 49(3): 612 - 617. [Abstract] [Full Text] [PDF]

				F. Herse, R. Dechend, N. K. Harsem, G. Wallukat, J. Janke, F. Qadri, L. Hering, D. N. Muller, F. C. Luft, and A. C. Staff Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia Hypertension, March 1, 2007; 49(3): 604 - 611. [Abstract] [Full Text] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, L. Xia, S. Abbasi, P. W. Hewett, C. Sun, A. Ahmed, R. E. Kellems, and Y. Xia Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy Circ. Res., January 5, 2007; 100(1): 88 - 95. [Abstract] [Full Text] [PDF]

				E. Shibata, R. W. Powers, A. Rajakumar, F. von Versen-Hoynck, M. J. Gallaher, D. L. Lykins, J. M. Roberts, and C. A. Hubel Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1009 - E1016. [Abstract] [Full Text] [PDF]

				F. Meziani, A. Tesse, E. David, M. C. Martinez, R. Wangesteen, F. Schneider, and R. Andriantsitohaina Shed Membrane Particles from Preeclamptic Women Generate Vascular Wall Inflammation and Blunt Vascular Contractility Am. J. Pathol., October 1, 2006; 169(4): 1473 - 1483. [Abstract] [Full Text] [PDF]

				H. Stepan, R. Faber, N. Wessel, G. Wallukat, H.-P. Schultheiss, and T. Walther Relation between Circulating Angiotensin II Type 1 Receptor Agonistic Autoantibodies and Soluble fms-Like Tyrosine Kinase 1 in the Pathogenesis of Preeclampsia J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2424 - 2427. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				R. Dechend, V. Homuth, G. Wallukat, D. N. Muller, M. Krause, J. Dudenhausen, H. Haller, and F. C. Luft Agonistic Antibodies Directed at the Angiotensin II, AT1 Receptor in Preeclampsia Reproductive Sciences, February 1, 2006; 13(2): 79 - 86. [Abstract] [PDF]

				T. Walther, G. Wallukat, A. Jank, S. Bartel, H.-P. Schultheiss, R. Faber, and H. Stepan Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature Hypertension, December 1, 2005; 46(6): 1275 - 1279. [Abstract] [Full Text] [PDF]

				C. Lam, K.-H. Lim, and S. A. Karumanchi Circulating Angiogenic Factors in the Pathogenesis and Prediction of Preeclampsia Hypertension, November 1, 2005; 46(5): 1077 - 1085. [Abstract] [Full Text] [PDF]

				R. Dechend, P. Gratze, G. Wallukat, E. Shagdarsuren, R. Plehm, J.-H. Brasen, A. Fiebeler, W. Schneider, S. Caluwaerts, L. Vercruysse, et al. Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia Hypertension, April 1, 2005; 45(4): 742 - 746. [Abstract] [Full Text] [PDF]

				M. Wolf, C. A. Hubel, C. Lam, M. Sampson, J. L. Ecker, R. B. Ness, A. Rajakumar, A. Daftary, A. S. M. Shakir, E. W. Seely, et al. Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6239 - 6243. [Abstract] [Full Text] [PDF]

				M. T. M. Raijmakers, R. Dechend, and L. Poston Oxidative Stress and Preeclampsia: Rationale for Antioxidant Clinical Trials Hypertension, October 1, 2004; 44(4): 374 - 380. [Abstract] [Full Text] [PDF]

				T. M. Thway, S. G. Shlykov, M.-C. Day, B. M. Sanborn, L. C. Gilstrap III, Y. Xia, and R. E. Kellems Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca2+ Mobilization Through Angiotensin Receptor Activation Circulation, September 21, 2004; 110(12): 1612 - 1619. [Abstract] [Full Text] [PDF]

				J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]

				F. C. Luft Pieces of the preeclampsia puzzle Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2209 - 2210. [Full Text] [PDF]