Response to Intrarenal Perfusion and Angiotensin II Levels Regulate In Vivo Angiotensin II Type 1 Receptor Imaging in the Kidney
We appreciate Dr Zhuo’s1 interest in our work on PET imaging of the renal AT1 receptor (AT1R) in a swine model of renal artery stenosis. One of the challenges of PET receptor studies is separation of signals representing nonspecific and receptor-specific radioligand accumulation. We had performed 3 measurements to support our concept that retention of [11C]KR31173 in late PET images was unlikely to represent nonspecific binding or free luminal [11C]KR311732:
We used the impulse response function to eliminate effects of radioligand recirculation.
We measured receptor expression with PET as well as in vitro and found significant correlation between the cortical in vivo binding paramete fret and the in vitro binding parameter Bmax (r=0.609; P<0.012).
Pretreatment with the potent AT1R inhibitor SK-1080 strongly suppressed radioligand binding and showed that 70% to 80% of binding was receptor specific.
In our study AT1R binding was markedly increased in pig kidneys with renal artery stenosis. Dr Amiri’s group3 cited by Dr Zhuo used binding assays to study the 2K1C rat model of renovascular hypertension and found increased angiotensin II (Ang II) production with a negative correlation between Ang II and AT1R. However, a positive correlation was described by Dr Zhuo’s group in Hypertension4: during Ang II hypertension, increased Ang II levels in renal cortical endosomes were associated with enhanced expression of the AT1R in endosomes and intermicrovillar clefts. Multiple factors are likely involved in the regulation of the AT1R, which include not only altered renal perfusion pressure but also the local release of Ang II and other tissue hormones. Thus, different regulation patterns observed in different animal models of hypertension were in part caused by comparison of in vitro and in vivo measurements or 2 in vitro techniques.
Another important observation by Dr Zhuo states that lisinopril treatment is expected to increase rather than abolish intrarenal AT1R binding.5 We documented increased AT1R binding in the hypoperfused kidney, an effect that was not further affected by an oral ACE inhibitor at a dose high enough to attenuate hypertension. There is no simple explanation for the difference between effect on blood pressure without effect on the AT1R. ACE inhibitors not only affect the RAS but also reduce the degradation of bradykinin, another modulator of AT1R expression. Tokuyama et al6 reported that in clipped kidneys, elevated Ang II is not suppressed by ACE inhibitors and disclose a novel mechanism that in the kidneys, Ang II may be generated through ACE-independent pathways, resulting in an “ACE-escape” phenomenon. Although the sample size in our article may not be sufficient to demonstrate differences between the untreated and treated subgroups, the results are assuring that, if the test becomes applicable in human renovascular hypertension, its sensitivity will not be affected by ACE inhibitor therapy at doses typically taken by human subjects.
Sources of Funding
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant RO1 DK50183, Interdisciplinary Small Animal Imaging grant 5R24CA092871.
Zhuo JL. Intrarenal perfusion and angiotensin II levels regulate in vivo angiotensin II type 1 receptor imaging in the kidney. Hypertension. 2008; 51: e52.
Xia J, Seckin E, Xiang Y, Vranesic M, Mathews WB, Hong K, Bluemke DA, Lerman LO, Szabo Z. Positron-emission tomography imaging of the angiotensin II subtype 1 receptor in swine renal artery stenosis. Hypertension. 2008; 51: 466–473.
Amiri F, Garcia R. Renal angiotensin II receptor regulation in two-kidney, one clip hypertensive rats: effect of ACE inhibition. Hypertension. 1997; 30: 337–344.
Zhuo JL, Imig JD, Hammond TG, Orengo S, Benes E, Navar LG. Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT1 receptor. Hypertension. 2002; 39: 116–121.
Li XC, Zhuo JL. In vivo regulation of AT1a receptor-mediated intracellular uptake of [125I]Val5-ANG II in the kidneys and adrenals of AT1a receptor-deficient mice. Am J Physiol Renal Physiol. 2008; 294: F293–F302.
Tokuyama H, Hayashi K, Matsuda H, Kubota E, Honda M, Okubo K, Takamatsu I, Tatematsu S, Ozawa Y, Wakino S, Saruta T. Differential regulation of elevated renal angiotensin II in chronic renal ischemia. Hypertension. 2002; 40: 34–40.