Response to On the Origin of Urinary Angiotensin II
We were pleased that our article titled, “Angiotensin II Type 1 Receptor–Mediated Augmentation of Urinary Excretion of Endogenous Angiotensin II in Val5-Angiotensin II–Infused Rats” generated sufficient interest to prompt van den Heuvel et al1 to suggest how we could distinguish between plasma- and kidney-derived angiotensin II (Ang II) in the urine. The focus of our study was to determine whether chronic Ang II infusion increased production of intrarenal Ang II as reflected by urinary excretion of endogenous Ang II.2 Importantly, during infusion of Val5-Ang II for 14 days, the plasma concentrations of Ile5-Ang II were markedly reduced compared with control rats3 because of the substantial reduction in plasma renin activity. Nevertheless, the kidney Ile5-Ang II contents were the same as the Val5-Ang II contents, and the urinary excretion of Ile5-Ang II increased progressively during Ang II infusion. In contrast, the plasma Ile5-Ang II concentrations were higher during candesartan treatment, but both kidney Ile5-Ang II content and urinary excretion of Ile5-Ang II were reduced compared with the rats not treated with candesartan. This marked dissociation between the circulating plasma levels and both the kidney contents and urinary excretion rates provide strong support for an AT1 receptor–mediated stimulation of intrarenal Ang II leading to intratubular Ang II formation and subsequent excretion in the urine. As indicated by the progressive increase in urinary Ang II excretion rate over several days, this process takes time and, thus, would not have been detected in the studies cited by van Kats et al,4 who used short-term infusion of 125I-Ang II.
During the initial phase of Val5-Ang II infusion, most of the intrarenal augmentation is because of AT1 receptor–mediated uptake from the circulation. However, after several days of infusion, there is a secondary phase dependent on augmentation of intrarenal angiotensinogen5 and collecting duct renin,6 which leads to the increased urinary Ang II excretion of endogenous Ang II. Because this is also dependent on AT1 receptor activation, this process was prevented by treatment with candesartan. Thus, the renal content of both endogenous Ile5-Ang II and Val5-Ang II was decreased by candesartan treatment, indicating that some of the Val5-Ang II accumulation was also dependent on AT1 receptor–mediated uptake. The ratio of plasma:kidney Val5-Ang II levels approached unity, suggesting that the AT1 receptor–independent components are primarily attributed to nonspecific equilibration between the plasma and the extracellular compartments in the kidney, including tubular fluid and the medulla. The Val5-Ang II excretion rates were generally lower in the candesartan-treated rats, also suggesting an AT1 receptor–mediated component responsible for the greater urinary Val5-Ang II in the rats that did not receive candesartan. It is tempting to suggest that the Val5-Ang II in the urine is derived not only by filtration but also by AT1 receptor–mediated secretion into the tubules, thus explaining why it was reduced during candesartan treatment. Further studies will determine the contribution of tubular secretion of Ang II to the tubular and urinary levels of Ang II.
Sources of Funding
This work was supported by grants from the National Heart, Lung, and Blood Institute (HL 26371); from the Health Excellence Fund of the Louisiana Board of Regents; and by a Centers of Biomedical Research Excellence grant (P20RR017659) from the Institutional Developmental Award program of the National Center for Research Resources.
van den Heuvel M, van Esch JHM, Danser AHJ. On the origin of urinary angiotensin II. Hypertension. 2010; 56: e45.
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.
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.
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.
Kobori H, Prieto-Carrasquero MC, Ozawa Y, Navar LG. AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension. Hypertension. 2004; 43: 1126–1132.