Morita Tatsuyori, Nakano Daisuke, Kitada Kento, Morimoto Satoshi, Ichihara Atsuhiro, Hitomi Hirofumi, Kobori Hiroyuki, Shiojima Ichiro, Nishiyama Akira
Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan; The Second Department of Internal Medicine, Kansai Medical University, Japan.
Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan.
Eur J Pharmacol. 2015 Jun 5;756:85-91. doi: 10.1016/j.ejphar.2015.03.053. Epub 2015 Mar 26.
We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses.
我们之前报道过，在小鼠中细胞周期蛋白依赖性激酶抑制剂p21的功能性缺失可减轻链脲佐菌素（STZ）诱导的1型糖尿病小鼠的肾细胞衰老。在本研究中，我们调查了铁螯合对1型糖尿病肾脏中肾细胞衰老和炎症的影响。经STZ处理的小鼠在第28周时肾脏中铁蓄积增加、肾小管细胞衰老及巨噬细胞浸润增加。给予仅去除膳食铁的地拉罗司可显著减轻近端肾小管中的铁蓄积及浸润的F4/80阳性细胞数量，而不影响血糖、血细胞比容或血红蛋白水平。然而，相比之下，地拉罗司并未影响肾细胞衰老。p21的缺失降低了肾小管铁蓄积，但未改变肾小管细胞衰老。有趣的是，经STZ处理的动物中另一种细胞周期蛋白依赖性激酶抑制剂p16增加。结果表明，1型糖尿病通过p21依赖性机制增加肾小管铁蓄积和巨噬细胞浸润，且膳食铁螯合可减轻这些反应。
