A combination of a PPAR-gamma agonist and an angiotensin II receptor blocker attenuates proinflammatory signaling and stimulates expression of Smad7 in human peritoneal mesothelial cells.

ABSTRACT

BACKGROUND: Human peritoneal mesothelial cells (HPMCs) have been shown to regulate the inflammatory response and the subsequent peritoneal extracellular matrix accumulation (ECM) induced by bio-incompatible peritoneal dialysis solutions. Recently, attention has been given to the possible antiinflammatory effect exhibited by angiotensin receptor blockers (ARB) or PPAR-gamma agonists in several tissues including glomerular. As no data on the potential role of these commonly used drugs in reducing peritoneal fibrosis exist, we examined the in vitro effects of an ARB (losartan) and a PPAR-gamma agonist (rosiglitazone) on inflammatory and profibrotic pathways in cultured HPMCs subjected to high glucose. METHODS: HPMCs were incubated for 48 hours with 3 different concentrations of glucose 5 mM (G5), 50 mM (G50) and 100 mM (G100), as well as G50 with either losartan (5 or 10 microM) and/or rosiglitazone (1 or 10 microM). IL-6, IL-8, VEGF and TGF-beta1 in the supernatants were measured by cytokine multiplex assays or ELISA. Smad7, the inhibitor of the TGF/Smad signaling pathway, was measured using immunocytochemistry. RESULTS: All the measured cytokines increased in proportion to increased concentration of glucose. Unexpectedly, this effect was not inhibited, but rather further enhanced, by rosiglitazone and losartan separately. However, only the combination of the two drugs had an inhibitory effect on TGF- beta1 and IL-6, while the expression of inhibitory Smad7 was increased. CONCLUSION: We conclude that high glucose exposure stimulates an inflammatory response in HPMCs in a dose-dependent manner. Rosiglitazone and losartan appear to have synergetic effects which could decrease fibrosis by inhibiting inflammation and regulating the TGF/Smad signaling pathway, but further studies are needed to elucidate the complex pathways modulated by these drugs.