NDT Advance Access originally published online on January 31, 2006
Nephrology Dialysis Transplantation 2006 21(5):1198-1204; doi:10.1093/ndt/gfk084
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats
1 Nephrology Division and 2 Department of Internal Medicine C, Assaf Harofeh Medical Center, Zerifin, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel
Correspondence and offprint requests to: J. Weissgarten, MD, Nephrology Division, Assaf Harofeh Medical Center, Zerifin 70300, Israel. Email: Weissgarten{at}asaf.health.gov.il
Background. The peroxisome proliferator activating nuclear receptors (PPAR) are activated in the context of inflammation, diabetes or normal pregnancy. Renal mesangial cells express PPAR-
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-ß1 production and nuclear factor 
B (NF-B) 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-ß and NF-B 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-ß synthesis and significant decrease in the levels of NF-B in mesangial cell nuclei were observed in all rosiglitazone treated groups.
Conclusions. PPAR- 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.
Keywords: angiotensin II; apoptosis; diabetes; PPAR; pregnancy; proliferation
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