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-gamma 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-beta1 production and nuclear factor kappaB (NF-kappaB) 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 3H-thymidine incorporation. Apoptosis was evaluated by TUNEL assay. AT-1/AT-2 receptor density was assessed by 125I-AT-2 labelling, TGF-beta and NF-kappaB 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-beta synthesis and significant decrease in the levels of NF-kappaB in mesangial cell nuclei were observed in all rosiglitazone treated groups.

Conclusions: PPAR-gamma 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.