Angiotensin type 1 and type 2 receptor blockade in chronic allograft nephropathy

Angiotensin-II (Ang-II) type 1 (AT1) receptor blockers may delay the progression of chronic allograft nephropathy (CAN). However, neither the optimal time for initiating AT1 receptor blockade in order to delay CAN potentially nor the role of Ang-II type 2 (AT2) receptors under AT1 receptor blockade is known. Both AT receptors can regulate p53 expression and apoptosis. We investigated what time of initiation with AT1 blockers most effectively delayed CAN as well as the role of the AT2 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 AT1 (candesartan) and/or AT2 (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 AT1 receptor blockade. A combined AT1/AT2 blocker treatment reduced CAN similarly to AT1 blocker treatment alone. The number of apoptotic cells and the level of p53 mRNA were significantly lower in long-term AT1 blocker-treated animals. In summary, AT1 receptor blockade delayed the progression of CAN, particularly in animals treated long term. Reduction of apoptosis could be related to these beneficial effects. The AT2 receptor does not appear to play an important role in CAN.