Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
Hino Hospital, Hino, Tottori 689-4504, Japan.
Int J Mol Sci. 2019 Dec 26;21(1):190. doi: 10.3390/ijms21010190.
Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin.
Male FLS- mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated.
The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis.
ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.
慢性肾脏病（CKD）和非酒精性脂肪性肝炎（NASH）是与代谢综合征密切相关的主要健康负担。人们假设 CKD 和 NASH 之间存在关联；然而，其潜在机制尚不清楚。肝细胞中的异位脂质沉积（ELD）会导致内质网（ER）应激，这在脂肪性肝炎的发展中起着重要作用。ELD 也被认为在肾脏损伤的发展中起作用。我们旨在研究 ELD 和 ER 应激在 CKD 发展中的作用，并评估钠-葡萄糖共转运蛋白-2 抑制剂伊格列净的疗效。
接受 vehicle 或伊格列净治疗的 FLS- 雄性小鼠，这种小鼠非常类似于 NASH 的病理生理学。评估代谢特征、肾脏组织学、ER 应激和凋亡信号。
伊格列净治疗的小鼠血清甘油三酯显著降低。伊格列净减少了肾小管中的 ELD。伊格列净还降低了 GRP78 和 CHOP、凋亡细胞和间质纤维化的表达水平。
ELD 通过 ER 应激引起肾脏损伤。伊格列净通过减少 NASH 模型小鼠中的 ELD 和 ER 应激改善了 CKD 的发病机制。我们的结果表明，伊格列净对 NASH 中的 CKD 具有治疗作用。
