靶向SAT1减轻高糖诱导的肾小管铁死亡和纤维化：对糖尿病肾病的意义

摘要(中文译文)

肾小管损伤和间质纤维化与糖尿病肾病（DKD）进展高度相关。肾小管上皮细胞铁死亡已成为DKD的关键机制之一。已发现，敲低亚精胺/精胺N1-乙酰转移酶1（SAT1）可减轻重复低剂量顺铂诱导的肾损伤和纤维化，更重要的是，沉默SAT1可抑制细胞对铁死亡的敏感性。然而，SAT1对DKD相关铁死亡的作用及其潜在机制尚不清楚。在本研究中，我们构建了高脂饮食/链脲佐菌素诱导的DKD小鼠模型和高糖（HG）损伤的HK-2细胞模型，旨在验证沉默SAT1是否通过调控铁死亡减轻DKD肾小管损伤。我们发现，SAT1在DKD小鼠肾脏和HG处理的HK-2细胞中表达上调。在DKD小鼠肾脏中观察到显著的肾小管损伤、纤维化、铁死亡和氧化应激。在体外功能缺失实验中，沉默SAT1抑制了HG诱导的HK-2细胞毒性、细胞外基质（ECM）合成和炎症。此外，沉默SAT1减少了HG激活的MDA和4-HNE生成，同时恢复了GSH水平。沉默SAT1还消除了HG激活的HK-2细胞铁死亡，表现为铁过载减少、脂质过氧化抑制以及铁死亡相关蛋白（SLC7A11、GPX4和TFR1）表达上调。在机制上，沉默SAT1促进了NRF2的核转位和表达。NRF2功能受损消除了沉默SAT1对HG刺激的HK-2细胞毒性、铁死亡和ECM积累的抑制作用。总体而言，SAT1/NRF2轴是DKD肾小管损伤的关键调控因子，抑制SAT1可能是DKD治疗的潜在靶点。

Abstract

Renal tubular damage and interstitial fibrosis are highly linked to diabetic kidney disease (DKD) progression. Ferroptosis in renal tubular epithelial cells has emerged as one of the key mechanisms of DKD. Spermidine/spermine N1-acetyltransferase 1 (SAT1) knockdown has been found to alleviate repetitive low-dose cisplatin-induced kidney damage and fibrosis, and importantly, SAT1 silencing represses cellular sensitivity to ferroptosis. However, the effect of SAT1 on DKD-associated ferroptosis and its potential mechanism remain understood. In this study, we constructed a high-fat diet/streptozotocin-induced DKD mouse model and a high glucose (HG)-injured HK-2 cell model with the aim of verifying whether SAT1 silencing attenuates DKD tubular damage by regulating ferroptosis. We found that SAT1 was upregulated in DKD mouse kidneys and HG-treated HK-2 cells. Significant tubular damage, fibrosis, ferroptosis, and oxidative stress were observed in DKD mouse kidneys. In an in vitro loss-of-function assay, SAT1 silencing suppressed HG-induced HK-2 cytotoxicity, extracellular matrix (ECM) synthesis, and inflammation. Additionally, SAT1 silencing decreased HG-activated MDA and 4-HNE production, while restoring GSH levels. SAT1 silencing also abrogated HG-activated ferroptosis in HK-2 cells, as evidenced by a reduction in iron overload, inhibition of lipid peroxidation, and upregulation of ferroptosis-related protein (SLC7A11, GPX4, and TFR1) expression. Mechanistically, SAT1 silencing facilitated nuclear translocation and expression of NRF2. Impairment of NRF2 function abrogated the inhibitory effects of SAT1 silencing on HG-stimulated HK-2 cytotoxicity, ferroptosis, and ECM accumulation. Overall, the SAT1/NRF2 axis is a critical regulator of tubular damage in DKD, and suppression of SAT1 may be an underlying target for DKD treatment.

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