10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

INVOLVEMENT OF THE ADIPOCYTE RENIN-ANGIOTENSIN SYSTEM IN HIV PROTEASE INHIBITOR IN VITRO TOXICITY. BENEFICIAL EFFECT OF ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS

Antiviral Therapy 2008; 13(Suppl. 4):A10 (abstract no. O-13)

F Boccara^1,2,3, M Auclair^1,2, A Cohen³, M Prott^1,2, C Lefevre^1,2, J Capeau^1,2 and M Caron^1,2
1INSERM, U680, Paris, France; ²Faculté de Médecine, Université Pierre et Marie Curie-Paris6, UMRS680, Paris, France; ³Department of Cardiology, Saint Antoine University Hospital, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie-Paris6, Paris, France

OBJECTIVES: Some HIV antiretrovirals can induce adipocyte dysfunction leading to insulin resistance in HIV-infected patients. In vitro, we have shown that some antihypertensive angiotensin II type 1 receptor (AT1R) blockers (ARBs) with PPARγ-activation properties (telmisartan and irbesartan) can prevent protease inhibitor-induced adipocyte dysfunction. Whether the specific adipocyte renin angiotensin (RAS) system is involved in these abnormalities remains to be determined.

METHODS: 3T3-F442A murine adipocytes and primary human adipocytes were incubated with two frequently prescribed protease inhibitors (PIs) in HIV-infected patients: lopinavir (LPVr; 10 µM) and atazanavir (ATVr; 5 µM) associated with ritonavir (2 µM). AT1R, AT2R, renin protein expression, AT1R cellular localization and angiotensin II effect on MAP kinases were investigated. We also evaluated AT1R expression on subcutaneous adipose tissue biopsies of HIV-infected patients treated with indinavir and compared with HIV controls. Finally, we determined the potential benefit of two ARBs (irbesartan and telmisartan) and rosiglitazone on PI-induced adipocyte RAS dysfunction.

RESULTS: In cultured murine and human adipocytes, PI combinations deregulated the protein expression of AT1R and AT2R (up and down-regulation, respectively), increased renin expression and accumulated AT1R at the plasma membrane. PI combinations also increased the effects of angiotensin II on MAP kinases resulting in constitutive activation of the adipocyte RAS. In subcutaneous biopsies, AT1R protein level was also increased in HIV-positive as compared with HIV-negative controls. The two ARBs (partial PPARγ agonists) prevented the PI effects on adipocyte RAS along with rosiglitazone (full PPARγ agonist). However, this beneficial effect was totally abolished by a PPARγ antagonist (PD).

CONCLUSIONS: Our study demonstrates for the first time that, in vitro, the adipose RAS is upregulated and activated by PIs, probably via a PPARγ pathway. In vivo experiments are warranted to evaluate the potential beneficial effect of PPARγ-activating ARBs on the PI-induced lipodystrophic syndrome and insulin resistance.

Download PDF of this abstract.

2008-11-06
O-13

Copyright © 2008 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.