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Human Adipose Tissue Expresses Angiotensinogen and Enzymes Required for Its Conversion to Angiotensin II¹

Research Centre for Endocrinology and Metabolism, (C.K., K.L., B.C., L.M.S.C.), Wallenberg Laboratory for Cardiovascular Research (M.O.), The Clinical Metabolic Laboratory (L.S.), Department of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Dr. Lena Carlsson, Research Centre for Endocrinology and Metabolism, Department of Internal Medicine, Gröna Strket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: lena.carlsson{at}ss.gu.se

	Abstract

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Angiotensin II regulates blood pressure and may affect adipogenesis and adipocyte metabolism. Angiotensin II is produced by cleavage of angiotensinogen by renin and angiotensin-converting enzyme in the circulation. In addition, angiotensin II may be produced in various tissues by enzymes of the renin-angiotensin system (RAS) or the nonrenin-angiotensin system (NRAS). We have analyzed the expression of angiotensinogen and enzymes required for its conversion to angiotensin II in human adipose tissue. Northern blot demonstrated angiotensinogen expression in adipose tissue from nine obese subjects. Western blot revealed a distinct band of expected size of the angiotensinogen protein (61 kDa) in isolated adipocytes. RT-PCR, followed by Southern blot, demonstrated renin expression in human adipose tissue. Angiotensin-converting enzyme messenger RNA was detected by RT-PCR, and the identity of the PCR products was verified by restriction enzyme cleavage. Transcripts for cathepsin D and cathepsin G, components of the NRAS, were detected by RT-PCR, verified by restriction enzyme cleavage. We conclude that human adipose tissue expresses angiotensinogen and enzymes of RAS and NRAS. This opens the possibility that angiotensinogen-derived peptides, produced in adipose tissue itself, may affect adipogenesis and play a role in the pathogenesis of obesity.

	Introduction

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ANGIOTENSIN II is an important regulator of blood pressure and of salt and water balance. Angiotensinogen, the precursor of angiotensin, is synthesized primarily by the liver, and is secreted into the circulation, where it is cleaved by renin to the decapeptide angiotensin I. Angiotensin I is subsequently converted to the octapeptide angiotensin II by angiotensin-converting enzyme (ACE) (for review, see Ref. 1).

In addition to the classical pathway of angiotensin II synthesis, tissue renin-angiotensin systems (RAS) have been identified in a number of organs, implying that various tissues have the ability to synthesize angiotensin II independently of the circulating RAS (2, 3). Locally produced angiotensin II has been suggested to participate in the control of tissue growth and development (4, 5). In adipose tissue, angiotensin II stimulates the production of prostacyclin, which in turn, triggers the conversion of preadipocytes to adipocytes (6, 7) and increases lipid synthesis and storage in adipocytes (8). Both rodent and human adipose tissue express angiotensinogen (9, 10), ACE (11, 12), and angiotensin II receptors (13), indicating the presence of some components of a local RAS in this tissue. However, generation of angiotensin II from angiotensinogen requires renin or alternative enzymes of the nonrenin-angiotensin systems (NRAS), such as cathepsin D, cathepsin G, tonin (14), or chymase (15). The cleavage of angiotensinogen by the enzymes of the NRAS results either in the formation of angiotensin I, for example by cathepsin D, or the direct formation of angiotensin II, by enzymes such as cathepsin G (14). So far, no information is available regarding the expression of renin or enzymes of the NRAS in human adipose tissue.

In this study, we have analyzed the expression of angiotensinogen and enzymes of the RAS and the NRAS in human adipose tissue. Our data show that angiotensinogen and genes encoding enzymes of the RAS and the NRAS are expressed in human adipose tissue. These results provide further support for a role of locally produced angiotensin in the regulation of adipose tissue growth and metabolism (16). In addition, adipose tissue-derived angiotensin could be a factor contributing to the association between obesity and hypertension (17, 18).

	Subjects and Methods

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Subjects and samples

The study was approved by the Ethical Committee of the Medical Faculty, University of Göteborg. Needle biopsies of abdominal sc adipose tissue were obtained from nine obese subjects; 40–62 yr old; body mass index, 29–45 kg/m². In addition, abdominal sc adipose tissue was obtained during surgery from a 58-yr-old, healthy female subject with a body mass index of 30.5 kg/m². Tissue samples were immediately frozen in liquid nitrogen and stored at -70 C until analyzed.

Isolation of adipocytes and stroma

Adipocytes and stroma were isolated from adipose tissue with collagenase, essentially as described previously (19).

RNA isolation

Total RNA was isolated as described by Chomczynski and Sacchi (20), with modifications described previously (21).

Northern blot

Northern blots were performed, as previously described (22), using 8 µg of total RNA and a ³²P-labeled antisense human angiotensinogen RNA probe. To verify the quality and amount of RNA, membranes were rehybridized with a probe for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The membrane was exposed on a Phosphor image screen (Molecular Dynamics, Inc., Sunnyvale, CA).

Probe synthesis

Angiotensinogen. A fragment (329 bp) of human angiotensinogen complementary DNA (cDNA) was amplified by PCR using primers listed in Table 1. The PCR product was subcloned into pCR II (Invitrogen, San Diego, CA) and sequenced with a Double-Stranded DNA Sequencing Kit (PE Applied Biosystems Division, Perkin-Elmer Corp., Foster City, CA). The vector was linearized with SpeI and used as template for synthesis of ³²P-labeled angiotensinogen complementary RNA with T7 polymerase, according to instructions from the manufacturer (Promega Corp., Madison, WI). Probes were purified on NICK Columns of Sephadex G-50 DNA grade (Pharmacia Biotech, Uppsala, Sweden).

RT-PCR

First-strand cDNA was generated from 2.5 µg denatured total RNA with 20 U avian myeloblastosis virus reverse transcriptase, 1 µg random hexamers and reagents from Promega Corp. (50 min at 42 C and 4 min at 72 C). PCR primers, specific for renin (23), ACE (24, 25), cathepsin D (26), and cathepsin G (27) cDNA, were designed to span at least one intron. PCR was performed in 1x PCR buffer with 0.4 mmol/L deoxynucleotide triphosphate (Boehringer Mannheim, Mannheim, Germany), 1 µmol/L each of sense and antisense primers (Table 1), 2.5 U Taq polymerase (Boehringer Mannheim), and 2.5 U Pfu (Stratagene, La Jolla, CA), in a final vol of 50 µL, using a GeneAmpPCR system 9600 (Perkin-Elmer Corp., Norwalk, CT). Cycle conditions are available on request. Control samples for detection of possible PCR contamination were included in all RT-PCR experiments and were routinely negative.

The PCR products were separated on agarose gels containing ethidium bromide and visualized by ultraviolet light. The identity of the PCR products was verified by restriction enzyme digestion (ACE, BstXI; cathepsin D, HindII; and cathepsin G, SmaI) or Southern blot (renin) (28). Southern blots were hybridized with a probe consisting of a 248-bp MspI/AvaII fragment of renin cDNA, lacking the sequences corresponding to the PCR primers. The DNA probe was labeled (Oligolabelling Kit, Pharmacia Biotech) using ³²P-CTP with a specific activity of 3000 Ci/mmol (NEN Life Science Products, Boston, MA) and purified by Nuc trap (Stratagene).

Western blot

Human adipose tissue, adipocytes, and stroma were homogenized at room temperature in lysis buffer [1 mmol/L EDTA, 10 mmol/L Tris (pH 7.5), 250 mmol/L sucrose, 1 mmol/L sodium ortovanadate, 0.6 mmol/L phenylmethylsulfonylfluoride, and 0.27 U/mL aprotinin (Sigma Chemical Co., St. Louis, MO)]. After centrifugation, the supernatant was transferred to a new tube and phenylmethylsulfonylfluoride and 1% Triton X-100 were added. The sample was rotated for 1 h at 4 C; and, after centrifugation, the supernatant was stored at -70 C.

Samples (9 µg protein) were mixed with Laemmli SDS loading buffer [50 mmol/L Tris HCl (pH 6.8), 100 mmol/L dithiothreitol, 2% SDS, 0.1% bromophenol blue, and 10% glycerol] and were separated on a homogeneous 20% PhastGel (Pharmacia Biotech). The proteins were transferred to a nitrocellulose membrane (Hybond-C; Amersham International, Little Chalfont, Buckinghamshire, UK) by the PhastSystem (Pharmacia Biotech). Immunological detection, using a monoclonal antihuman angiotensinogen antibody, was performed, essentially as described previously (29).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Detection of angiotensinogen in human adipose tissue

A possible paracrine or autocrine role of the angiotensin system in adipose tissue is dependent on local production of angiotensinogen and enzymes capable of converting it to the effector peptide, angiotensin II (Fig. 1). We therefore analyzed the expression of angiotensinogen in biopsies of human adipose tissue. Northern blot analysis, using 8 µg total RNA and a ³²P-labeled antisense human angiotensinogen RNA probe, showed the presence of a single band with an estimated size of 2.0 kb. The angiotensinogen transcript was detectable in all of the nine obese subjects included in the study (Fig. 2). Furthermore, Western blot analysis, using a monoclonal antibody directed against human angiotensinogen, revealed a distinct band, corresponding to the expected size of the angiotensinogen protein (61 kDa) in lysate of isolated human adipocytes, whereas lysate of stroma gave a weaker signal (Fig. 3).

View larger version (20K): [in this window] [in a new window]   Figure 1. Schematic representation of pathways for angiotensin II production. Angiotensinogen can be converted to angiotensin II, either via RAS or via NRAS. Examples of NRAS enzymes are given in the figure.

View larger version (42K): [in this window] [in a new window]   Figure 2. Northern blot analysis of angiotensinogen expression in sc adipose tissue from nine obese human subjects. The membrane was rehybridized with a probe for the housekeeping gene GAPDH.

View larger version (39K): [in this window] [in a new window]   Figure 3. Western blot analysis of angiotensinogen in isolated human adipocytes and in stroma.

We then analyzed the expression of enzymes of RAS in adipose tissue. RT-PCR, with primers specific for human renin cDNA, revealed products of expected size (404 bp) in RNA extracted from adipose tissue, isolated adipocytes, and stroma. The identity of the PCR products was verified by Southern blot analysis, using an internal renin cDNA probe (Fig. 4).

View larger version (37K): [in this window] [in a new window]   Figure 4. Renin expression in human adipose tissue, isolated adipocytes, and stroma, analyzed by RT-PCR followed by Southern blot.

View larger version (45K): [in this window] [in a new window]   Figure 5. ACE expression in human adipose tissue, detected by RT-PCR (a). The identity of the PCR products was verified by restriction enzyme digestion (b). c, Negative control.

In the next experiments, we analyzed the expression of cathepsin D and cathepsin G, as examples of enzymes of NRAS. RT-PCR, using primers specific for human cathepsin D and cathepsin G cDNA, resulted in PCR products of the expected sizes, when total RNA extracted from human adipose tissue (Fig. 6), isolated adipocytes, or stroma (data not shown) was used as template. The identity of the cathepsin D and cathepsin G PCR products was verified by restriction enzyme digestion.

View larger version (40K): [in this window] [in a new window]   Figure 6. RT-PCR of mRNA encoding cathepsin D (a, upper panel) and cathepsin G (a, lower panel). The identity of the PCR products was verified by restriction enzyme digestion (b). c, Negative control.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Angiotensinogen expression was detectable in all patients in our study and in 7 of 12 patients in an earlier report by others (10). The finding that angiotensinogen is expressed in human adipose tissue is in agreement with data obtained in rodents (9) and in cultured rodent cell lines (31, 32, 33). At the protein level, we found that angiotensinogen is clearly detectable in extracts of human adipocytes and, to a lesser degree, also is present in the stroma fraction of human adipose tissue. The higher production of angiotensinogen by mature adipocytes is in agreement with experiments on rodent cell lines (3T3-L1 and 3T3-F442A), suggesting that the appearance of angiotensinogen synthesis and secretion coincides with differentiation and markers of adipocyte function (32, 33). The detection of small amounts of angiotensinogen in the stroma fraction in our study may reflect the presence of several different cell types in this preparation, including some contamination with adipocytes and/or preadipocytes.

This is the first study demonstrating renin expression in adipose tissue. However, renin and renin-like activity have been detected in several tissues (3, 34), although the major site of renin production is the kidney. As for angiotensinogen, renin mRNA was most abundant in the adipocyte fraction of adipose tissue. The expression of all components of the RAS in human adipose tissue [i.e. angiotensinogen (Ref. 10 and this study), renin (this study), ACE (Ref. 12 and this study), and angiotensin II receptors (13)] opens the possibility for paracrine/autocrine actions of this system in this tissue.

In addition to circulating and local RAS, angiotensin II may also be produced by the action of enzymes of NRAS (14). As examples of this alternative pathway, we examined the expression of cathepsin D and cathepsin G. Like renin, cathepsin D is a member of the aspartyl protease family (35), and it converts angiotensinogen to angiotensin I. Cathepsin D is widely expressed in mammalian cells (35), and we here show that this also includes human adipose tissue. Cathepsin G, an enzyme capable of generating angiotensin II, was also expressed in human adipose tissue.

We conclude that angiotensinogen and the enzymes involved in its conversion to angiotensin II of both the RAS and NRAS pathways are expressed in human adipose tissue. These results provide further support for the idea that angiotensin II, produced locally in adipose tissue, may be involved in the regulation of adipogenesis and lipid metabolism and in the development of diseases secondary to obesity, such as hypertension. Clarification of the relative importance of the various enzymes of RAS and NRAS in adipose tissue may open new possibilities for therapeutic intervention.

	Acknowledgments

 
We thank Dr. Inger Rubin (University of Copenhagen, Denmark) for kindly providing antihuman angiotensinogen antibody.

	Footnotes

 
¹ This study was supported by the Swedish Medical Research Council (Grants 11285, 11502, 11576, 11331, and 05239), The Swedish Medical Society, The Göteborg Medical Society, Swedish Society for Medical Research, Kungl och Hvitfeldtska Stipendiestiftelsen, and Stiftelsen för Fonden för Studerande av Läkarvetenskap vid Sahlgrenska Sjukhuset.

Received April 28, 1998.

Revised July 1, 1998.

Accepted August 10, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Reid IA, Morris BJ, Ganong WF. 1978 The renin-angiotensin system. Annu Rev Physiol. 40:377–410.[CrossRef][Medline]
2. Phillips MI, Speakman EA, Kimura B. 1993 Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept. 43:1–20.[CrossRef][Medline]
3. Paul M, Wagner J, Dzau VJ. 1993 Gene expression of the renin-angiotensin system in human tissues. Quantitative analysis by the polymerase chain reaction. J Clin Invest. 91:2058–2064.
4. Timmermans PBMWM, Wong PC, Chiu AT, et al. 1993 Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 45:205–251.[Medline]
5. Morgan L, Pipkin FB, Kalsheker N. 1996 Angiotensinogen: molecular biology, biochemistry and physiology. Int J Biochem Cell Biol. 28:1211–1222.[CrossRef][Medline]
6. Négrel R, Gaillard D, Ailhaud G. 1989 Prostacyclin as a potent effector of adipose-cell differentiation. Biochem J. 257:399–405.[Medline]
7. Darimont C, Vassaux G, Ailhaud G, Négrel R. 1994 Differentiation of preadipose cells: paracrine role of prostacyclin upon stimulation of adipose cells by angiotensin-II. Endocrinology. 135:2030–2036.[Abstract]
8. Jones BH, Standridge MK, Moustaïd N. 1997 Angiotensin II increases lipogenesis in 3T3–L1 and human adipose cells. Endocrinology. 138:1512–1519.[Abstract/Free Full Text]
9. Cassis LA, Saye JA, Peach MJ. 1988 Location and regulation of rat angiotensinogen messenger RNA. Hypertension. 11:591–596.[Abstract/Free Full Text]
10. Jones BH, Standridge MK, Taylor JW, Moustaïd N. 1997 Angiotensinogen gene expression in adipose tissue: analysis of obese models and hormonal and nutritional control. Am J Physiol. 273:R236–R242.
11. Crandall DL, Gordon G, Herzlinger HE, et al. 1992 Transforming growth factor alpha and atrial natriuretic peptide in white adipose tissue depots in rats. Eur J Clin Invest. 22:676–680.[Medline]
12. Jonsson JR, Game PA, Head RJ, Frewin DB. 1994 The expression and localisation of the angiotensin-converting enzyme mRNA in human adipose tissue. Blood Press. 3:72–75.[Medline]
13. Crandall DL, Herzlinger HE, Saunders BD, Armellino DC, Kral JG. 1994 Distribution of angiotensin II receptors in rat and human adipocytes. J Lipid Res. 35:1378–1385.[Abstract]
14. Genest J, Cantin M, Garcia R, et al. 1983 Extrarenal angiotensin-forming enzymes. Clin Exp Hypertens. 5:1065–1080.
15. Wolny A, Clozel JP, Rein J, et al. 1997 Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res. 80:219–227.[Abstract/Free Full Text]
16. Harp JB, DiGirolamo M. 1995 Components of the renin-angiotensin system in adipose tissue: changes with maturation and adipose mass enlargement. J Gerontol A Biol Sci Med Sci. 50A:B270–B276.
17. Sjöström CD, Lissner L, Sjöström L. 1997 Relationships between changes in body composition and changes in cardiovascular risk factors: the SOS intervention study. Obes Res. 5:519–530.[Medline]
18. Alonso-Galicia M, Brands MW, Zappe DH, Hall JE. 1996 Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity. Hypertension. 28:1047–1054.[Abstract/Free Full Text]
19. Smith U, Sjöström L, Björntorp P. 1972 Comparison of two methods for determining human adipose cell size. J Lipid Res. 13:822–824.[Abstract]
20. Chomczynski P, Sacchi N. 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 162:156–159.[Medline]
21. Carlsson B, Lindell K, Gabrielsson B, et al. 1997 Obese (ob) gene defects are rare in human obesity. Obes Res. 5:30–35.[Medline]
22. Carlsson B, Billig H, Rymo L, Isaksson OGP. 1990 Expression of the growth hormone-binding protein messenger RNA in the liver and extrahepatic tissues in the rat: co-expression with the growth hormone receptor. Mol Cell Endocrinol. 73:R1–R6.
23. Hobart PM, Fogliano M, O‘Connor BA, Schaefer IM, Chirgwin JM. 1984 Human renin gene: structure and sequence analysis. Proc Natl Acad Sci USA. 81:5026–5030.[Abstract/Free Full Text]
24. Soubrier F, Alhenc-Gelas F, Hubert C, et al. 1988 Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci USA. 85:9386–9390.[Abstract/Free Full Text]
25. Hubert C, Houot A-M, Corvol P, Soubrier F. 1991 Structure of the angiotensin I-converting enzyme gene. J Biol Chem. 266:15377–15383.[Abstract/Free Full Text]
26. Redecker B, Heckendorf B, Grosch H-W, Mersmann G, Hasilik A. 1991 Molecular organization of the human cathepsin D gene. DNA Cell Biol. 10:423–431.[Medline]
27. Hohn PA, Popescu NC, Hanson RD, Salvesen G, Ley TJ. 1989 Genomic organization and chromosomal localization of the human cathepsin G gene. J Biol Chem. 264:13412–13419.[Abstract/Free Full Text]
28. Brown T. 1993 Analysis of DNA sequences by blotting and hybridization. In: Ausubel FM, Brent R, Kingston RE, et al., eds. Current protocols in molecular biology. Vol 1. New York: Wiley; 2.9.1–2.9.15.
29. Rubin I, Lykkegaard S, Olsen AA, Selmer J, Ballegaard M. 1988 Monoclonal antibodies against human angiotensinogen, their characterization and use in an angiotensinogen enzyme linked immunosorbent assay. J Immunoassay. 9:257–274.[Medline]
30. Frederich Jr RC, Kahn BB, Peach MJ, Flier JS. 1992 Tissue-specific nutritional regulation of angiotensinogen in adipose tissue. Hypertension. 19:339–344.[Abstract/Free Full Text]
31. Aubert J, Darimont C, Safonova I, Ailhaud G, Négrel R. 1997 Regulation by glucocorticoids of angiotensinogen gene expression and secretion in adipose cells. Biochem J. 328:701–706.
32. Saye JA, Cassis LA, Sturgill TW, Lynch KR, Peach MJ. 1989 Angiotensinogen gene expression in 3T3–L1 cells. Am J Physiol. 256:C448–C451.
33. Saye JA, Lynch KR, Peach MJ. 1990 Changes in angiotensinogen messenger RNA in differentiating 3T3–F442A adipocytes. Hypertension. 15:867–871.[Abstract/Free Full Text]
34. Mulrow PJ. 1992 Adrenal renin: regulation and function. Front Neuroendocrinol. 13:47–60.[Medline]
35. Faust PL, Kornfeld S, Chirgwin JM. 1985 Cloning and sequence analysis of cDNA for human cathepsin D. Proc Natl Acad Sci USA. 82:4910–4914.[Abstract/Free Full Text]

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				A. Wiecek, F. Kokot, J. Chudek, and M. Adamczak The adipose tissue--a novel endocrine organ of interest to the nephrologist Nephrol. Dial. Transplant., February 1, 2002; 17(2): 191 - 195. [Full Text] [PDF]

				F. Massiera, J. Seydoux, A. Geloen, A. Quignard-Boulange, S. Turban, P. Saint-Marc, A. Fukamizu, R. Negrel, G. Ailhaud, and M. Teboul Angiotensinogen-Deficient Mice Exhibit Impairment of Diet-Induced Weight Gain with Alteration in Adipose Tissue Development and Increased Locomotor Activity Endocrinology, December 1, 2001; 142(12): 5220 - 5225. [Abstract] [Full Text] [PDF]

				D. B. Savage, C. P. Sewter, E. S. Klenk, D. G. Segal, A. Vidal-Puig, R. V. Considine, and S. O'Rahilly Resistin / Fizz3 Expression in Relation to Obesity and Peroxisome Proliferator-Activated Receptor-{gamma} Action in Humans Diabetes, October 1, 2001; 50(10): 2199 - 2202. [Abstract] [Full Text]

				A. Sonmez, U. Kisa, G. Uckaya, T. Eyileten, B. Comert, B. Koc, F. Kocabalkan, and M. Ozata Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension Journal of Renin-Angiotensin-Aldosterone System, June 1, 2001; 2(2): 112 - 116. [Abstract] [PDF]

				C. Perry, N. Sattar, and J. Petrie Review: Adipose tissue: passive sump or active pump? The British Journal of Diabetes & Vascular Disease, March 1, 2001; 1(2): 110 - 114. [Abstract] [PDF]

				A. M Sharma and S. Engeli The renin-angiotensin system in obesity hypertension Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S114 - S119. [PDF]

				P. Saint-Marc, L. P. Kozak, G. Ailhaud, C. Darimont, and R. Negrel Angiotensin II as a Trophic Factor of White Adipose Tissue: Stimulation of Adipose Cell Formation Endocrinology, January 1, 2001; 142(1): 487 - 492. [Abstract] [Full Text] [PDF]

				B. L. Wajchenberg Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome Endocr. Rev., December 1, 2000; 21(6): 697 - 738. [Abstract] [Full Text]

				V. Serazin-Leroy, M. Morot, P. de Mazancourt, and Y. Giudicelli Androgen regulation and site specificity of angiotensinogen gene expression and secretion in rat adipocytes Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1398 - E1405. [Abstract] [Full Text] [PDF]

				P. Stenvinkel Leptin and blood pressure--is there a link? Nephrol. Dial. Transplant., August 1, 2000; 15(8): 1115 - 1117. [Full Text] [PDF]

S. Engeli, R. Negrel, and A. M. Sharma Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1270 - 1277.