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Angiotensin II in the Rat Adrenal Zona Glomerulosa (Renin Release/Subceilular Fractionation/Renin-Angiotensin System) HIDENORI URATA, MAHESH C

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Angiotensin II in the Rat Adrenal Zona Glomerulosa (Renin Release/Subceilular Fractionation/Renin-Angiotensin System) HIDENORI URATA, MAHESH C Proc. Nati. Acad. Sci. USA Vol. 85, pp. 8251-8255, November 1988 Medical Sciences Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa (renin release/subceilular fractionation/renin-angiotensin system) HIDENORI URATA, MAHESH C. KHOSLA, F. MERLIN BUMPUS, AND AHSAN HUSAIN* Department of Heart and Hypertension Research, Research Institute of The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-5071 Communicated by Irvine H. Page, July 18, 1988 ABSTRACT Based on the observation that high levels of system in the adrenal ZG. The major goal of this study was renin and angiotensin II (Ang II) are found in the adrenal zona to directly examine the previously proposed models of Ang glomerulosa (ZG), it has been postulated that Ang H is formed II formation (intracellular versus extracellular) in the rat intracellularly by the renin-converting enzyme cascade in this adrenal ZG. We also describe a biochemical mechanism for tissue. To test this hypothesis, we examined renin-angiotensin inactivation of Ang II in the ZG. system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (LR-Ang II) were observed in vesicular fractions but were not colocalized. MATERIALS AND METHODS In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang 11-containing Subcellular Fractionation Studies. Female Sprague-Dawley vesicular fractions. These data do not support the hypothesis rats (-300 g) were used in this study. Adrenal glands were that Ang II is formed intracellularly within the renin- dissected on ice to yield the capsular ZG and the decapsular containing vesicles of the ZG. Rather, since modulatable renin zona fasciculata medulla tissue. The ZG tissue was sus- release from adrenal ZG slices was observed and renin activity pended in 0.25 M sucrose and homogenized in a glass/Teflon was found in dense vesicular fractions (33-39% sucrose), it is homogenizer. The homogenate was centrifuged at 800 x g likely that Ang II formation in the ZG is extracellular and for 10 min to remove unbroken cells and nuclei, and the initiated by the release of vesicular renin. Receptor-mediated resultant supernatant was layered on either a discontinuous endocytosis and subsequent degradation of Ang II in ZG sucrose density gradient system 1 (3 ml each of 65%, 37%, lysosomes have been shown by others. The presence of IR-Ang and 15% sucrose) or system 2 (2 ml each of 65%, 39%, 33%, II in light vesicular fractions (15% sucrose) and the finding of and 15% sucrose) and centrifuged at 85,000 x g for 1 hr at a high correlation between ZG IR-Ang H and Ang II receptor 4°C. After centrifugation, the gradients were fractionated levels suggest that the primary occurrence ofthis peptide in the from the bottom. Renin, angiotensinogen, and converting ZG is by receptor-mediated endocytosis. In ZG lysosomal enzyme were measured in subcellular fractions after vesic- fractions '2MI-labeled Ang II was degraded to '2,I-labeled ular disruption. To disrupt vesicles in subcellular fractions, des-[Phe8]Ang II. Since Ang II antibodies do not recognize distilled water was added to a portion of each fraction (1:1, des-[Phe8]Ang II, these rmdings explain why IR-Ang II in the vol/vol) and the samples were freeze-thawed three times. ZG is due predominantly to Ang II and not to its C-terminal Measurement of Renin-Angiotensin System Components. immunoreactive fragments. Renin activity was measured by RIA (New England Nuclear) ofthe generated Ang I after incubation with excess rat plasma angiotensinogen at pH 7.4 as described (4). The incubations The secretion of aldosterone from the adrenal zona glome- were for 16 hr at 37°C in 100 mM NaH2PO4 buffer containing rulosa (ZG) appears to be predominantly under endocrine 5 mM N-ethylmaleimide, 0.5 mM phenylmethylsulfonyl flu- control imposed by the renal renin-angiotensin system and oride, and 10 mM EDTA to prevent Ang I breakdown. the pituitary corticotropin (ACTH) system (1). During the last Angiotensinogen concentration was estimated by Ang I two decades the possibility of autocrine and/or paracrine produced after incubating the sample with excess rat kidney regulation of aldosterone secretion by angiotensin II (Ang II) renin for 1 hr at 37°C in the renin incubation buffer. The has gained support in view of the demonstrations of the indirect method for estimation of angiotensinogen was used components of the renin-angiotensin system and Ang II since it, unlike the direct RIA, quantifies only the prohor- receptors in the adrenal gland (2-5). Recent studies have mone and not the des-Ang I angiotensinogen. Using a 100-,ul provided considerable information on the regulation of ad- sample, the minimum level of angiotensinogen that could be renal Ang II and renin, the primary processing enzyme ofthe detected by this assay was 20 pM. Converting enzyme renin-angiotensin system. Interpretation of the regulation activity was measured with a radioassay kit (Ventrex Labo- data, however, has been difficult. For example, in potassium ratories, Portland, ME). Acid protease activity was measured chloride-loaded rats adrenal renin activity is increased and by the method ofAnson (7) with [14C]hemoglobin as substrate adrenal Ang II is reduced (3); thus, it is not clear whether in in 500 mM sodium acetate buffer (pH 3.2). Protein concen- potassium chloride-loaded rats the adrenal production ofAng tration was measured by the method of Lowry et al. (8). For II is increased or decreased. A similar divergence between the measurement ofAng I and Ang II in subcellular fractions, renin and Ang II has been reported in the rat adrenal ZG after 200 mM HCl/ethanol (1:3) was added to a portion of each bilateral nephrectomy (5, 6). The elucidation of the mecha- fraction (10:1, vol/vol) and the mixture was mixed vigorously nism of formation of Ang II in the adrenal gland is therefore for 5 min, clarified by centrifugation, and lyophilized. The necessary and is likely to be an important first step in residues were resuspended in 100 mM NaH2PO4 buffer (pH understanding the physiological role ofthe renin-angiotensin Abbreviations: Ang II and I, angiotensins II and I; IR-Ang II, The publication costs of this article were defrayed in part by page charge immunoreactive Ang II; Ang-(1-7), des-[Phe8]Ang II; ZG, zona payment. This article must therefore be hereby marked "advertisement" glomerulosa; 'l25-Ang II, "N-I-labeled Ang II; ACTH, corticotropin. in accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 8251 Downloaded by guest on September 29, 2021 8252 Medical Sciences: Urata et al. Proc. Natl. Acad. Sci. USA 85 (1988) 7.4), and Ang I and Ang II in the solution were partially RESULTS purified on a C18 Sep-Pak cartridge and then quantified by RIAs as described (4). Subcellular Localization of Renin-Angiotensin System Com- Adrenal Slice Studies. Fresh adrenal capsules containing ponents. Subcellular fractionation of the rat adrenal ZG by the ZG were obtained from rats nephrectomized 48 hr sucrose gradient system 1 yielded a discrete renin activity were and peak (fractions 5-8) at the 37%/65% sucrose interface (Fig. previously. Individual capsules cut into quarters 1). In two different separations, the average recovery of the preincubated in 2 ml of Krebs-Ringer buffer without bicar- measured renin activity and immunoreactive-Ang II (IR-Ang bonate containing 10 mM Hepes and 1 mg of glucose per ml II) applied to the gradient was 84% and 75%, respectively. (pH 7.4) at 370C for 30 min. Four adrenal capsules were used About 60% of the recovered renin activity and <5% of the per incubation tube. The supernatant was discarded and recovered IR-Ang II was present in the renin peak. The replaced with 2 ml of Krebs-Ringer buffer without bicarbon- majority (>80%) of the IR-Ang II was recovered in a broad ate containing 10 mM Hepes (pH 7.4), 0.1 mg ofbovine serum peak (fractions 11-19) within the 15% and 37% sucrose albumin per ml, with or without 55 nM epinephrine, 50 nM layers. To examine the presence of the other components of ACTH, or 20 mM K+, and incubated at 370C for 3 hr. The the renin-angiotensin system in the renin-containing subcel- tubes were then centrifuged at 1900 x g for 5 min at 4TC. lular fractions, the rat adrenal ZG tissue was fractionated by Supernatants were stored at - 900C until assayed for renin sucrose gradient system 2, which was more shallow than activity. sucrose gradient system 1. When gradient system 2 was used, 12,I-Labeled Ang II ('25I-Ang II) Metabolism Studies. Ang renin activity was enriched in the 33% and 39% sucrose layers II, des-[Phe8]Ang II [Ang-(1-7)], des-[Pro7,Phe8]Ang II [Ang- (Fig. 2, fractions 4-6). In some renin-containing fractions, (1-6)], des-[His6,Pro7,Phe8]Ang II [Ang-(1-5)], des-[Ile5, such as fraction 3 in Fig. 2, a small amount ofangiotensinogen His6,Pro7,Phe8]Ang II [Ang-(1-4)], des-[Asp']Ang II [Ang- was observed. The level of angiotensinogen obtained in this (2-8)], des-[Asp1,Arg2]Ang II [Ang-(3-8)], and des-[Asp', fraction was <1/10,000th of the Km of the renin-angioten- Arg2,Val3]Ang II [Ang-(4-8)] were synthesized and purified sinogen reaction, which is -1 puM. However, IR-Ang I, as described (9). These peptides were all labeled with 1251 by converting enzyme activity, and angiotensinogen were all the lactoperoxidase method and the monoiodinated products undetectable in the peak renin-containing fractions (Fig.
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