On the Origin of Urinary Angiotensin II
To the Editor:
With great interest we read the publication by Shao et al,1 who propose that angiotensin (Ang) II type 1 (AT1) receptor stimulation in the kidney results in urinary Ang II excretion. The authors have used an elegant approach, infusing rats with Val5-Ang II to allow a clear distinction from endogenous Ile5-Ang II, here denoted as Ang II. Val5-Ang II is believed to have the same properties as Ang II.
We have followed a similar approach and infused 125I-labeled Ang II in pigs to distinguish it from endogenous Ang II.2 In these studies, 125I-Ang II accumulation in the kidney, largely, if not exclusively, depended on AT1 receptors, as demonstrated by a >90% reduction in the renal tissue/plasma concentration ratio of 125I-Ang II after pretreatment with the AT1 receptor blocker eprosartan.3 Recent experiments showing low or undetectable renal Ang II levels in AT1 receptor knockout animals further support the dependency of renal Ang II accumulation on AT1 receptors.4 In addition, the porcine renal tissue/plasma concentration ratio of endogenous Ang II decreased by ≈90% after eprosartan pretreatment,3 thus confirming that renal 125I-Ang II accumulation fully resembles that of endogenous Ang II.
In the study by Shao et al,1 the renal tissue/plasma ratio of endogenous Ang II decreased by >90% after candesartan treatment (from 358/24 to 21/157), identical to our results in pigs. Yet, the ratio of Val5-Ang II was virtually unchanged after candesartan treatment (385/283 versus 242/217). This demonstrates that the renal accumulation of Val5-Ang II, unlike that of Ang II and 125I-Ang II, largely occurs in an AT1 receptor–independent manner, at least when infused at a rate of 80 ng/min. One explanation for this discrepancy may be that this rate is above the rate required to obtain (near) complete renal AT1 receptor occupancy. In agreement with this concept, Val5-Ang II suppressed plasma renin activity by >95%. Yet, endogenous plasma Ang II was either unaltered1 or increased.5
According to Figure 6,1 urinary Val5-Ang II excretion without candesartan amounted to 3 to 7 pmol/24 hours. Urinary volumes ranged from 11 to 38 mL/24 hours, and thus the urinary Val5-Ang II concentrations were 80 to 636 fmol/mL. This equals the Val5-Ang II concentration range in plasma. Because Val5-Ang II cannot be made in the kidney, and assuming that circulating Val5-Ang II reaches urine to the same degree as circulating Ang II, it appears that urine minimally contains the same Ang II levels as plasma based on filtration and/or tubular secretion of circulating Ang II. Consequently, by using the Val5-Ang II urine/plasma concentration ratio, it should be possible to distinguish plasma- and kidney-derived Ang II in urine. The same procedure might be followed during candesartan treatment so that one gets an indication of the AT1 receptor blockade-induced changes in the urinary washout of circulating Ang II and renal Ang II. Given the identical urinary excretion rates of Val5-Ang II and Ang II during candesartan treatment, as well as their comparable plasma levels during such treatment, it can already be predicted that candesartan reduces the net release of Ang II from renal tissue sites into urine to 0.
Shao W, Seth DM, Navar LG. Angiotensin II type 1 receptor–mediated augmentation of urinary excretion of endogenous angiotensin II in Val5-angiotensin II–infused rats. Hypertension. 2010; 56: 378–383.
van Kats JP, de Lannoy LM, Danser AHJ, van Meegen JR, Verdouw PD, Schalekamp MADH. Angiotensin II type 1 (AT1) receptor-mediated accumulation of angiotensin II in tissues and its intracellular half-life in vivo. Hypertension. 1997; 30: 42–49.
van Esch JHM, Gembardt F, Sterner-Kock A, Heringer-Walther S, Le TH, Lassner D, Stijnen T, Coffman TM, Schultheiss HP, Danser AHJ, Walther T. Cardiac phenotype and angiotensin II levels in AT1a, AT1b, and AT2 receptor single, double, and triple knockouts. Cardiovasc Res. 2010; 86: 401–409.
Shao W, Seth DM, Navar LG. Augmentation of endogenous intrarenal angiotensin II levels in Val5-ANG II-infused rats. Am J Physiol Renal Physiol. 2009; 296: F1067–F1071.