Department of Pathology, Hebei Medical University, Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China; Center of Metabolic Diseases and Cancer research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China.
Laboratorical center for Electron Microscopy, Hebei Medical University, Shijiazhuang, China.
Int J Biochem Cell Biol. 2022 Aug;149:106247. doi: 10.1016/j.biocel.2022.106247. Epub 2022 Jun 23.
Lipid accumulation and progressive necroinflammation play pivotal roles in the development of diabetic nephropathy. C1q tumour necrosis factor-related protein-3 (CTRP3) is an adipokine with pleiotropic functions in cell proliferation, glucose and lipid metabolism, and inflammation. However, the mechanism and involvement of CTRP3 in lipid metabolism and the necroinflammation of renal tubular cells remain unclear. Here, we report that CTRP3 expression decreased in a time- and concentration-dependent manner in high glucose-stimulated HK-2 cells. We noted that the overexpression of CTRP3 or recombinant CTRP3 (rCTRP3) treatment prevented high glucose-induced lipid accumulation by inhibiting the expression of sterol regulatory element-binding protein-1 and increasing the expression of peroxisome proliferator-activated receptor-α and ATP-binding cassette A1. Moreover, the nucleotide-binding oligomerisation domain-like receptor protein 3-mediated inflammatory response and mixed lineage kinase domain-like protein-dependent necroinflammation were inhibited by CTRP3 overexpression or rCTRP3 treatment in HK-2 cells cultured in high glucose. Furthermore, lipotoxicity-induced by palmitic acid was found to be involved in necroinflammation in HK-2 cells, and CTRP3 displayed the same protective effect. CTRP3 also activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, whereas adenine 9-β-D-arabinofuranoside, an AMPK inhibitor, replicated the protective effects of CTRP3. Besides, using kidney biopsies from patients with diabetes, we found that decreased CTRP3 expression was accompanied by increased lipid deposition, as well as the structural and functional injury of renal tubular cells. Our findings demonstrate that CTRP3 affects lipid metabolism and necroinflammation in renal tubular cells via the AMPK signalling pathway. Thus, CTRP3 may be a potential therapeutic target in diabetic renal injury.
脂质积累和进行性坏死性炎症在糖尿病肾病的发生发展中起着关键作用。C1q 肿瘤坏死因子相关蛋白-3（CTRP3）是一种脂肪因子，具有细胞增殖、葡萄糖和脂质代谢以及炎症等多种功能。然而，CTRP3 在脂代谢和肾小管细胞坏死性炎症中的机制和作用尚不清楚。在这里，我们报告 CTRP3 的表达在高糖刺激的 HK-2 细胞中呈时间和浓度依赖性下降。我们注意到，CTRP3 的过表达或重组 CTRP3（rCTRP3）治疗可通过抑制固醇调节元件结合蛋白-1 的表达和增加过氧化物酶体增殖物激活受体-α和三磷酸腺苷结合盒 A1 的表达来防止高糖诱导的脂质积累。此外，CTRP3 的过表达或 rCTRP3 治疗可抑制高糖培养的 HK-2 细胞中核苷酸结合寡聚化结构域样受体蛋白 3 介导的炎症反应和混合谱系激酶结构域样蛋白依赖性坏死性炎症。此外，我们发现棕榈酸诱导的脂毒性参与了 HK-2 细胞的坏死性炎症，而 CTRP3 则显示出相同的保护作用。CTRP3 还激活了腺苷单磷酸激活蛋白激酶（AMPK）通路，而 AMPK 抑制剂腺嘌呤 9-β-D-阿拉伯呋喃糖苷复制了 CTRP3 的保护作用。此外，我们使用糖尿病患者的肾活检样本发现，CTRP3 表达降低伴随着脂质沉积增加，以及肾小管细胞的结构和功能损伤。我们的研究结果表明，CTRP3 通过 AMPK 信号通路影响肾小管细胞的脂代谢和坏死性炎症。因此，CTRP3 可能是糖尿病肾损伤的潜在治疗靶点。
