Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids
Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids
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DOI：
10.34067/kid.0000772019
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发表时间：
2020-08-01
期刊：
影响因子：
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通讯作者：
Maruyama, Toru
中科院分区：
文献类型：
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作者：
Imafuku, Tadashi;Watanabe, Hiroshi;Maruyama, Toru
肾近端小管病变在肾脏疾病中起重要作用，但其分子机制尚不完全清楚。由于近端小管细胞在重吸收过程中消耗大量能量，脂肪酸（FAs）与近端小管病变的关系一直备受关注。本研究的目的是探讨肾FA组成变化与肾小管病变之间的关系。方法采用顺铂所致肾毒性小鼠作为AKI模型，5/6肾切除小鼠作为CKD模型。采用气相色谱-质谱法测定小鼠肾脏FA组成。人小管上皮细胞（HK-2细胞）用于体外研究。结果AKI小鼠肾脏硬脂酸（C18:0）升高，棕榈酸（C16:0）降低，长链FA延长酶elov16表达升高。在CKD小鼠中也得到了类似的结果。通过诱导内质网应激，我们发现C18:0比C16:0具有更高的小管毒性。在HK-2细胞中使用表达Elovl6的腺病毒或表达Elovl6的siRNA，我们证明Elovl6表达的增加通过增加C18:0来促进小管病变。Elovl6基因敲除抑制了血清肌酐水平升高、肾内质网应激以及通常在5/6肾切除术后出现的炎症。高级氧化蛋白产物（AOPPs），特别是氧化白蛋白，被发现通过mTORC1/SREBP1途径诱导Elovl6。结论AOPPs可能通过诱导Elovl6扰乱肾脏FAs而导致肾小管病变。AOPPs-Elovl6系统引起的肾FAs紊乱可能是治疗小管病的潜在靶点。
Background Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy.Methods Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies.Results In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway.Conclusions AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.