Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function
Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function
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DOI：
10.1096/fj.201900217r
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发表时间：
2019-08
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通讯作者：
H. Nagasu;Yuji Sogawa;Kengo Kidokoro;S. Itano;Toshiya Yamamoto;M. Satoh;Tamaki Sasaki;Takafumi Suzuki;Masayuki Yamamoto;W. C. Wigley;Joel W. Proksch;Colin J. Meyer;N. Kashihara
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作者：
H. Nagasu;Yuji Sogawa;Kengo Kidokoro;S. Itano;Toshiya Yamamoto;M. Satoh;Tamaki Sasaki;Takafumi Suzuki;Masayuki Yamamoto;W. C. Wigley;Joel W. Proksch;Colin J. Meyer;N. Kashihara
多项临床研究表明，甲基巴多索龙是核因子红细胞2相关因子2（Nrf 2）的有效激活剂，可有效提高慢性肾脏疾病患者的肾小球滤过率。然而，Nrf 2激活剂是否可以通过抗炎和抗氧化应激机制保护肾小管免受蛋白尿诱导的肾小管损伤尚不清楚。使用癌症研究所衍生的肾小球肾炎（ICGN）肾病小鼠模型，我们检查了二氢-CDDO-三氟乙基酰胺（dh 404）（一种啮齿动物可耐受的巴多索酮甲基类似物）在保护肾小管上皮细胞方面的作用; dh 404显著抑制了ICGN小鼠肾上皮细胞的肾小管上皮细胞损伤。ICGN小鼠的肾小管上皮细胞显示线粒体的大小和数量减少，以及嵴结构的破坏，而线粒体的数量和超微结构通过dh 404处理得以维持。为了进一步确定dh 404对线粒体功能的影响，我们在体外使用人近端肾小管细胞。白蛋白和游离脂肪酸刺激增加线粒体活性氧（ROS）。然而，dh 404施用减少了线粒体ROS。我们的数据显示，dh 404显著降低了蛋白尿诱导的肾小管细胞线粒体损伤，表明改善的氧化还原平衡和线粒体功能以及炎症抑制是Nrf 2激活剂（包括甲基巴多索龙）在糖尿病肾病中的细胞保护机制的基础。Nagasu，H.，Sogawa，Y.，Kidokoro，K.，Itano，S.，山本，T.，Satoh，M.，Sasaki，T.，铃木，T.，山本，M.，威格利，W. C.的方法，Proksch，J.W.，迈耶角J.，Kashihara，N. Bardoxolone甲基类似物通过调节线粒体功能减轻蛋白尿诱导的肾小管损伤FASEB J. 33，12253 - 12263（2019）。www.fasebj.org
Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2‐related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria‐induced tubular damage via anti‐inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research‐derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro‐CDDO‐trifluoroethyl amide (dh404), a rodent‐tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria‐induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.—Nagasu, H., Sogawa, Y., Kidokoro, K.,Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria‐induced tubular damage by modulating mitochondrial function. FASEB J. 33, 12253‐12263 (2019). www.fasebj.org