Endocrine Abstracts (2002) 3 OC28

Rosiglitazone inhibits insulin-mediated rise in angiotensinogen expression and angiotensin II secretion in human subcutaneous adipocytes

AL Harte1, PG McTernan1, SA Smith2, AH Barnett1 & S Kumar1

1Division of Medical Sciences, Medicine, University of Birmingham, Birmingham, UK; 2Glaxo SmithKline, Harlow, UK.

The renin-angiotensin system (RAS)is important for the regulation of blood pressure with its blockade shown to reduce the vascular complications of diabetes. Adipose tissue expresses the RAS system and may contribute to obesity associated hypertension. Our previous in vitro studies have demonstrated that in human adipose tissue production of both angiotensinogen (AGT) and the active metabolite angiotensin II are stimulated by insulin. The present study investigated the influence of insulin co-treated with an insulin enhancer, rosiglitazone (RSG), on both the expression of angiotensinogen and the secretion of angiotensin II in human subcutaneous (Sc) abdominal fat (n=12). Isolated Sc adipocytes were treated with varying doses of insulin (1nM-100nM) in combination with rosiglitazone (RSG 10-8M), and with RSG alone (10-10M-10-6M) for 48hrs. Following treatment, adipocytes, and secreted products in the conditioned media, were harvested. Western blotting was performed on the protein extracted from the adipocytes to determine AGT expression. ELISAs were performed on the collected media to determine the secretion of angiotensin II. Increasing doses of insulin (Ins) co-treated with RSG (10-8M) reduced angiotensin II secretion (Control: 214.3±12.6 pg/mL; Ins1nM/RSG: 59.34±6.26 pg/mL*; Ins 10nM: 83.11±9.34 pg/mL*; Ins100nM: 102.10±22.72 pg/mL;*p<0.05). Insulin co-treated with RSG also reduced AGT protein expression compared with insulin alone. Increasing doses of RSG alone significantly suppressed angiotensin II secretion (RSG 10-10M: 74.32±13.83 pg/mL*; RSG 10-8M: 104.45±14.35 pg/mL*; RSG 10-6M 146.91±15.18 pg/mL). Similar findings were observed with AGT protein expression for RSG. In summary, insulin co-treated with RSG reduced the insulin mediated rise in angiotensin II secretion relative to control in vitro. Clinical studies are needed to confirm these effects in vivo and to study long-term effects in combination with anti-hypertensive drugs that block the RAS.

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