Weissgarten Joshua, Berman Sylvia, Efrati Shai, Rapoport Micha, Averbukh Zhan, Feldman Leonid
Nephrology Division, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Nephrol Dial Transplant. 2006 May;21(5):1198-204. doi: 10.1093/ndt/gfk084. Epub 2006 Jan 31.
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.
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.
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.
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.
过氧化物酶体增殖物激活核受体（PPAR）在炎症、糖尿病或正常妊娠的情况下被激活。肾系膜细胞表达PPAR-γ，激活后能够发挥抗炎作用。我们研究了在妊娠（无论是否合并糖尿病）情况下，罗格列酮体内治疗对培养的肾系膜细胞中血管紧张素II（A-II）刺激的炎症表现的影响，如增殖、凋亡、转化生长因子-β1（TGF-β1）产生和核因子κB（NF-κB）激活。
从以下几组分离系膜细胞，给予或不给予5mg/kg罗格列酮20天：正常对照组、正常妊娠大鼠、链脲佐菌素诱导的糖尿病大鼠和妊娠糖尿病大鼠。通过3H-胸腺嘧啶核苷掺入评估增殖。通过TUNEL法评估凋亡。通过125I-AT-2标记评估AT-1/AT-2受体密度，通过特异性酶联免疫吸附测定法评估TGF-β和NF-κB。
罗格列酮预处理导致对照组、妊娠大鼠和非妊娠糖尿病动物培养物中的增殖、凋亡显著降低，对A-II刺激的反应性降低。在处死前接受罗格列酮的妊娠糖尿病组中，对A-II的反应性完全减弱。在所有罗格列酮治疗组中，均观察到系膜细胞核中TGF-β合成适度减弱，NF-κB水平显著降低。
罗格列酮激活PPAR-γ导致炎症特征表现降低，包括抑制系膜细胞增殖、下调凋亡以及减弱对A-II的反应性。这些抗炎性肾脏保护作用在妊娠糖尿病动物的培养物中表现最为明显。这些观察结果的治疗相关性有待进一步研究。
