Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies.
BACKGROUND
We previously described angiotensin II type 1 receptor-activating antibodies (AT1R-Abs) in renal transplant recipients with vascular rejection and malignant hypertension. In this study, we tested the hypothesis that AT1R-Abs can cause renal artery contraction by AT1R activation with renal ischemia representing a key permissive factor and therefore contribute to renal pathologic condition.


METHODS
Isolated renal and mesenteric arteries from Lewis rats were incubated with purified AT1R-Abs from patients with human leukocyte antigen antibody-negative vascular rejection. Vascular contraction was measured using small vessel myography. The measurements were repeated with renal arteries derived from native kidneys subjected to ischemia-reperfusion or after transplantation in a low-responder Fischer 344-to-Lewis rat kidney-transplantation model.


RESULTS
AT1R-Abs acted in a vascular bed-specific manner and caused small contractions only in native rat renal arteries but not in mesenteric arteries. AT1R-Abs did not alter the vascular reactivity to phenylephrine, angiotensin II, or acetylcholine in native renal arteries. In contrast, AT1R-Abs caused a pronounced (>10-fold) contraction of renal arteries after ischemia and after allogeneic transplantation. Pretreatment with pharmacologic AT1R blocker only partially inhibited the AT1R-Abs-induced contraction, which was almost completely abolished by neutralizing peptides targeting epitopes of AT1R-Abs on the second loop of AT1R.


CONCLUSIONS
These data demonstrate that AT1R-Abs can induce renal vascular contraction under predisposing conditions such as in ischemic or transplanted kidneys. Neutralizing antibodies against specific epitopes in the AT1R can ameliorate this contraction.
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Berlin, Germany. ilukitsc@tulane.edu
Ivo
I
Lukitsch
Jasmin
J
Kehr
Lyubov
L
Chaykovska
Gerd
G
Wallukat
Melina
M
Nieminen-Kelhä
Vecihi
V
Batuman
Duska
D
Dragun
Maik
M
Gollasch
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply*; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D012077:Renal Artery / Q000502:physiology*; D014661:Vasoconstriction
D000906:Antibodies; D044140:Receptor, Angiotensin, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases