Angiotensin type 1 and type 2 receptor blockade in chronic allograft nephropathy.
Angiotensin-II (Ang-II) type 1 (AT(1)) receptor blockers may delay the progression of chronic allograft nephropathy (CAN). However, neither the optimal time for initiating AT(1) receptor blockade in order to delay CAN potentially nor the role of Ang-II type 2 (AT(2)) receptors under AT(1) receptor blockade is known. Both AT receptors can regulate p53 expression and apoptosis. We investigated what time of initiation with AT(1) blockers most effectively delayed CAN as well as the role of the AT(2) receptor, and how angiotensin receptor blockade affected apoptosis and its regulating factors in this context in a rat model. Kidneys of Fisher (F344) rats were transplanted into Lewis rats. Animals were treated with AT(1) (candesartan) and/or AT(2) (PD123319) receptor antagonists, a calcium channel blocker, or vehicle (treatment periods: day -7 before to week 24 after transplantation (long term), week 12 to week 24 (late), day -7 to day +5 (early)) and observed the animals for 24 weeks. Reduction of proteinuria, grade of CAN, and number of apoptotic cells was most pronounced in animals receiving long-term AT(1) receptor blockade. A combined AT(1)/AT(2) blocker treatment reduced CAN similarly to AT(1) blocker treatment alone. The number of apoptotic cells and the level of p53 mRNA were significantly lower in long-term AT(1) blocker-treated animals. In summary, AT(1) receptor blockade delayed the progression of CAN, particularly in animals treated long term. Reduction of apoptosis could be related to these beneficial effects. The AT(2) receptor does not appear to play an important role in CAN.
Lutz
J
J
Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
Risch
K
K
Liu
S
S
Antus
B
B
Schmaderer
C
C
Roos
M
M
Ouyang
N
N
Lehmann
M
M
Heemann
U
U
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002908:Chronic Disease; D004347:Drug Interactions; D005500:Follow-Up Studies; D007093:Imidazoles / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D009404:Nephrotic Syndrome / Q000209:etiology / Q000517:prevention & control*; D011507:Proteinuria / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014184:Transplantation, Homologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016159:Tumor Suppressor Protein p53; C073402:PD 123319; C081643:candesartan