Published Online
on February 7, 2005

A more recent version of this article appeared on April 1, 2005

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Submitted on October 13, 2004
Revised on November 3, 2004

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

Ralf Dechend; Petra Gratze; Gerd Wallukat; Erdenechimeg Shagdarsuren; Ralf Plehm; Jan-Hinrich Bräsen; Anette Fiebeler; Wolfgang Schneider; Silvia Caluwaerts; Lisbeth Vercruysse; Robert Pijnenborg; Friedrich C. Luft^*; and Dominik N. Müller

From Medical Faculty of the Charité (R.D., P.G., E.S., R.P., H.-H.B., A.F., W.S., F.C.L.), Franz Volhard Clinic and Department of Pathology, HELIOS-Klinikum Berlin, Germany; Max Delbrück Center for Molecular Medicine (G.W., D.N.M.), Berlin, Germany; and Experimenteel Laboratorium Gynecologie (S.C., L.V., R.P.), Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium.

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

Abstract--We used rats transgenic for the human angiotensinogen (hAogen) gene and the human renin (hRen) gene and crossed the strains to produce a model of preeclampsia in the dams. The female (n=9) hAogen x male hRen cross had severe (telemetry-measured) hypertension and albuminuria, which developed during the last trimester of pregnancy and subsided after delivery. The converse cross (n=9) and control (n=9) SD rats did not. We demonstrated that the female hAogen x male hRen cross had agonistic antibodies capable of activating the angiotensin (Ang) II AT1 receptor (AT1R-AA) and defined the epitope on the receptor’s second extracellular loop. The phenomenon also occurs in humans with preeclampsia. The rats displayed renal histology reminiscent of preeclampsia, including fibrin deposition confined to the glomeruli. The complement system was activated in glomeruli and IgG deposits were present that may represent AT1R-AA. Finally, we observed an atherosis-like lesion in the spiral arteries of the placental bed, which we called placental-bed arteriolosclerosis. Our model may be relevant to preeclampsia in humans.

Key words: preeclampsia • rats, transgenic • antibodies • immune systems • renin-angiotensin system

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