Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats

Abstract

Background. The peroxisome proliferator activating nuclear receptors (PPAR) are activated in the context of inflammation, diabetes or normal pregnancy. Renal mesangial cells express PPAR-γ which upon activation are capable of exerting anti-inflammatory effects. We investigated the effect of in vivo treatment by rosiglitazone on angiotensin II (A-II) stimulated manifestations of inflammation in cultured renal mesangial cells, such as proliferation, apoptosis, TGF-β1 production and nuclear factor κB (NF-κB) activation, in the situation of pregnancies, complicated or not with diabetes. Methods. Mesangial cells were isolated from the following groups, receiving or not 5 mg/kg rosiglitazone for 20 days: normal controls, normal pregnant rats, those with streptozotocine induced diabetes and pregnant diabetic rats. Proliferation was assessed by 3 H-thymidine incorporation. Apoptosis was evaluated by TUNEL assay. AT-1/AT-2 receptor density was assessed by 125 I-AT-2 labelling, TGF-β and NF-κB by specific ELISAs. Results. Rosiglitazone pretreatment resulted in significantly decreased proliferation, apoptosis and reduced responsiveness to A-II stimulation in cultures from controls, pregnant rats and non-pregnant diabetic animals. In the pregnant diabetic group which received rosiglitazone prior to sacrifice, responsiveness to A-II was completely blunted. Moderate attenuation of TGF-β synthesis and significant decrease in the levels of NF-κB in mesangial cell nuclei were observed in all rosiglitazone treated groups. Conclusions. PPAR-γ activation by rosiglitazone resulted in decreased manifestation of inflammatory hallmarks, including inhibition of mesangial cell proliferation, downregulation of apoptosis and blunted responsiveness to A-II. These anti-inflammatory renoprotective effects were maximally expressed in cultures from pregnant diabetic animals. The therapeutic relevance of these observations is a matter of further investigations. © 2006 Oxford University Press.