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.