Agonistic autoantibodies to the AT1 receptor in a transgenic rat model of preeclampsia.
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.
Dechend
Ralf
R
Medical Faculty of the Charité, Franz Volhard Clinic and Department of Pathology, HELIOS-Klinikum Berlin, Germany.
Gratze
Petra
P
Wallukat
Gerd
G
Shagdarsuren
Erdenechimeg
E
Plehm
Ralf
R
Bräsen
Jan-Hinrich
JH
Fiebeler
Anette
A
Schneider
Wolfgang
W
Caluwaerts
Silvia
S
Vercruysse
Lisbeth
L
Pijnenborg
Robert
R
Luft
Friedrich C
FC
Müller
Dominik N
DN
D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001323:Autoantibodies / Q000276:immunology*; D003167:Complement Activation; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011225:Pre-Eclampsia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000276:immunology*; D012083:Renin / Q000235:genetics
D001323:Autoantibodies; D007074:Immunoglobulin G; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D005337:Fibrin; D012083:Renin