HIV protease inhibitors activate the adipocyte renin angiotensin system.
BACKGROUND
HIV-infected patients under antiretroviral therapy that includes HIV protease inhibitors (PIs) are prone to develop a complex metabolic syndrome including insulin resistance, lipodystrophy and hypertension. Whether hypertension and cardiovascular events could result from the adipocyte renin angiotensin system (RAS) overactivation has never been investigated.


METHODS
Primary human adipocytes and 3T3-F442A murine adipocytes were incubated with lopinavir or atazanavir boosted with ritonavir, with or without the angiotensin II type-1 receptor (AT1R) blockers (ARBs), irbesartan or telmisartan, and the peroxysome proliferator-activated receptor-gamma (PPAR-gamma) regulators, rosiglitazone and GW9662. Adipose RAS activation and adipocyte functions were evaluated.


RESULTS
The ritonavir-boosted PIs activated the adipose RAS in human and murine adipocytes as shown by the overexpression of AT1R protein, angiotensinogen messenger RNA and the amplified effect of angiotensin II on extracellular signal-regulated kinase 1/2 activity. ARBs prevented the PI effect on RAS activation (AT1R overexpression and signalling) and adipocyte functions (dedifferentiation, insulin resistance, oxidative stress and inflammation). Consistent with a role of PPAR-gamma signalling in PI-induced RAS activation, the PPAR-gamma agonist (rosiglitazone) normalized PI-induced AT1R overexpression and adipocyte dysfunction. Conversely, the PPAR-gamma antagonist (GW9662) induced AT1R overexpression and reduced the beneficial effect of telmisartan on PI toxicity.


CONCLUSIONS
We report that two frequently prescribed PI combinations could activate the adipose RAS in cultured cells, in part through a PPAR-gamma-dependant signalling pathway. Our data suggest a role for the adipose RAS in the development of hypertension in HIV-infected patients under PI treatment, and point out the potential use of ARBs to decrease PI adverse effects.
Boccara
Franck
F
Faculté de Médecine Saint Antoine, INSERM, UMRS938, Paris, France. franck.boccara@sat.aphp.fr
Auclair
Martine
M
Cohen
Ariel
A
Lefèvre
Chloé
C
Prot
Mathieu
M
Bastard
Jean-Philippe
JP
Capeau
Jacqueline
J
Caron-Debarle
Martine
M
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D000077405:Irbesartan; D061466:Lopinavir; D051379:Mice; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology; D011744:Pyrimidinones / Q000009:adverse effects / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D019438:Ritonavir / Q000009:adverse effects / Q000494:pharmacology; D000077333:Telmisartan; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D047495:PPAR gamma; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D000077405:Irbesartan; D019438:Ritonavir; D000077333:Telmisartan