Zhu Pengfei, Ma Haijian, Cui Shichao, Zhou Xiqiao, Xu Weilong, Yu Jiangyi, Li Jingya
The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing 210000, China.
State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Pharmaceuticals (Basel). 2022 Mar 31;15(4):434. doi: 10.3390/ph15040434.
Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease.
目前，慢性肾脏病（CKD）是最常见的疾病之一；由于其高死亡率，它也是对人类健康的严重威胁，其治疗仍然是一项重大的临床挑战。线粒体动态平衡失调在CKD的发展中起重要作用。ZLN005是我们实验室研发的一种新型过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）激活剂。为了探究ZLN005在体内和体外是否能预防CKD，本研究分别采用了单侧输尿管梗阻（UUO）模型和转化生长因子-β1（TGF-β1）处理的肾小管上皮细胞（TECs）。我们发现，与对照小鼠相比，给予ZLN005的UUO小鼠肾脏损伤较轻，这表现为UUO小鼠肾脏中纤维化生物标志物的表达降低。ZLN005治疗还减轻了TGF-β1诱导的TECs纤维化表型和脂质积累。我们的研究表明，ZLN005治疗至少部分通过激活PGC-1α改善了线粒体动态平衡，从而维持线粒体功能和能量平衡。总之，ZLN005治疗可改善UUO诱导的肾纤维化，为慢性肾脏病的线粒体靶向治疗提供了理论支持。
