Dr. Rodney Kellems, Professor and Chairman

Department of Biochemistry and Molecular Biology
Program in Biochemistry and Molecular Biology

University of Texas-Houston Medical School
P.O. Box 20708 - Houston, Texas 77225
(713) 500-6124 - Fax (713-500-0652)
email:Rodney.E.Kellems@uth.tmc.edu

Ph.D., Princeton Univeristy
NIH Postdoctoral Fellowship, Stanford University
Research Career Development Award, National Institutes of Health

ANGIOTENSIN RECEPTORS, AUTOANTIBODIES, & DISEASE

Angiotensin receptor activating autoantibodies and preeclampsia.
Preeclampsia is the leading cause of death due to pregnancy with clinical consequences involving severe life-threatening vascular abnormalities. The molecular mechanisms responsible for the pathogenesis of preeclampsia remain poorly understood. We found that women with preeclampsia harbor autoantibodies capable of activating the angiotensin receptor, AT1R. We showed that these autoantibodies bind to a specific seven amino acid sequence on the second extracellular loop of the angiotensin receptor. Overall, our results provide strong evidence that these autoantibodies activate AT1 receptors on a variety of cells and thereby contribute to many features of the disease. Research is underway to determine the immunological origin of these autoantibodies and the mechanism by which they activate the AT1 receptor. This project is being carried out in collaboration with Dr. Yang Xia.

Angiotensin receptor activating autoantibodies (AT1-AAs) may underlie many features of preeclampsia. AT1-AAs from preeclamptic patients activate angiotensin receptors (AT1R) on the surface of many cell types and may be responsible for many features of this serious pregnancy disorder. We have shown that antibody-induced receptor activation results in the mobilization of intracellular calcium and the activation of many genes. We propose that AT1-AAs activate AT1 receptors by promoting receptor homodimerization. ROS, reactive oxygen species. SMC, smooth muscle cells; EC, endothelial cells.

Irani R.A., Zhang Y., Zhou C.C., Blackwell S.C., Hicks M.J., Ramin S.M., Kellems R.E., Xia Y. Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-alpha signaling. Hypertension. 55:1246-53, 2010.

Zhou C.C., Irani R.A., Zhang Y., Blackwell S.C., Mi T., Wen J., Shelat H., Geng Y.J., Ramin S.M., Kellems R.E., Xia Y. Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-alpha induction contributes to increased soluble endoglin production in preeclampsia. Circulation. 121:436-44, 2010.

Siddiqui A.H., Irani R.A., Blackwell S.C., Ramin S.M., Kellems R.E., Xia Y. Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: correlation with disease severity. Hypertension. 55:386-93, 2010.

Wen J., Jiang X., Dai Y., Zhang Y., Tang Y., Sun H., Mi T., Phatarpekar P.V., Kellems R.E., Blackburn M.R., Xia Y. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J. 24:740-9, 2010.

Irani R.A., Zhang Y., Blackwell S.C., Zhou C.C., Ramin S.M., Kellems R.E., Xia Y. The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia. J Exp Med. 206:2809-22, 2009.

Wen J., Jiang X., Dai Y., Zhang Y., Tang Y., Sun H., Mi T., Kellems R.E., Blackburn M.R., Xia Y. Adenosine Deaminase Enzyme Therapy Prevents and Reverses the Heightened Cavernosal Relaxation in Priapism. J Sex Med. 2009 Oct 20.

Xia Y., Kellems R.E. Is preeclampsia an autoimmune disease? Clin Immunol. 133:1-12. 2009.

Zhou C.C., Zhang Y, Irani R.A., Zhang H, Mi T, Popek E.J., Hicks M.J., Ramin S.M., Kellems R.E., Xia Y: Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med. 14: 855-862, 2008.

Carbonaro, D.A., Jin, X., Cotoi, D., Mi, T., Yu, X.J., Skelton, D.C., Dorey, F., Kellems, R.E., Blackburn, M.R., Kohn, D.B.: Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunological reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion. Blood, 111: 5745-54, 2008.

Mi, T., Abbasi, S., Zhang, H., Uray, K., Chunn, J.L., Xia, L.W., Molina, J.G., Weisbrodt, N.W., Kellems, R.E., Blackburn, M.R., Xia, Y.: Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest. 118:1491-501, 2008.

Zhou, C.C., Ahmad, S., Mi, T., Abbasi, S., Xia, L., Day, M.C., Ramin, S.M., Ahmed, A., Kellems, R.E., Xia, Y.: 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. 51:1010-9. 2008.

Xia, Y., Zhou, C.C., Ramin, S.M., Kellems, R.E.: Angiotensin receptors, autoimmunity, and preeclampsia.
J Immunol. 179:3391-5. 2007.

Mohsenin, A., Mi, T., Xia, Y., Kellems, R.E., Chen, J.F., Blackburn, M.R..: Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice. Am J Physiol Lung Cell Mol Physiol, 293:L753-61, 2007.

Xia, Y., Ramin, S.M., Kellems, R.E.: Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of preeclampsia. Hypertension. 50:269-75, 2007.

Zhou, C.C., Ahmad, S., Mi, T., Xia, L., Abbasi, S., Hewett, P.W., Sun, C., Ahmed, A., Kellems, R.E., Xia, Y.: Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res, 100:88-95, 2007.

Carbonaro, D.A., Jin, X., Petersen, D., Wang, X., Dorey, F., Kil, K.S., Aldrich, M., Blackburn, M.R., Kellems, R.E., Kohn, D.: In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knock-out mice: A novel form of enzyme replacement therapy for ADA-deficiency. Molecular Therapy, 13:1110-1120, 2006.

Abbasi, S., Lee, J.D., Su, B., Chang, X., Alcorn, J., Yang, J., Kellems, R.E., Xia, Y.: Protein kinase medicated regulation of calcineurin through the phosphorylation of modulatory calcineurin interacting protein 1. J Biol Chem, 281:7717-7726, 2006.

Schaubach, B.M., Wen, H.Y., Kellems, R.E.: Regulation of murine adenosine deaminase gene expression in the placenta by transcription factor RUNX1. Placenta, 27:269-277, 2006.

Chunn, J.L., Mohsenin, A., Young, H.W., Lee, C.G., Elias, J.A., Kellems, R.E., Blackburn, M.R.: Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290:L579-587, 2006.

Bobst, S.M., Day, M.-C., Gilstrap, L.C.3rd, Xia, Y., Kellems, R.E.: Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion. Am J Hypertension, 18(3):330-336, 2005.

Search PubMed for a complete list of Dr. Kellem's publications.