Department of Pathology, Cangzhou Hospital of Integrated TCM‑WM, Cangzhou, Hebei 061001, P.R. China.
The Office of Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11872. Epub 2021 Feb 4.
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element‑binding protein 1 (SREBP‑1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP‑1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP‑1 upregulation. Diabetic mice and high glucose‑cultured HKC cells were chosen to detect the expression of FBXW7 and SREBP‑1 using immunohistochemistry, western blotting and PCR. The present study demonstrated that F‑box and WD repeat domain containing 7 (FBXW7) expression was decreased in renal tubular cells of diabetic mice. Moreover, the co‑expression of FBXW7 and SREBP‑1 was observed in renal tubular cells, but not in the glomeruli. High glucose‑induced the downregulation of FBXW7 expression in in vitro cultured HKC cells, which was accompanied by SREBP‑1 upregulation. In addition, overexpression of FBXW7 in HKC cells led to SREBP‑1 downregulation. By contrast, knockdown of FBXW7 caused SREBP‑1 upregulation in HKC cells. It was found that the PI3K/Akt signaling pathway was activated in high glucose‑stimulated HKC cells, and inhibition of PI3K/Akt pathway using LY294002 increased FBXW7 expression and decreased SREBP‑1 expression. Taken together, the present results suggested that FBXW7 mediated high glucose‑induced SREBP‑1 expression in renal tubular cells of DN, under the regulation of the PI3K/Akt signaling pathway.
糖尿病肾病（DN）是糖尿病的一种严重并发症，脂质代谢异常在 DN 的发病机制中起关键作用。固醇调节元件结合蛋白 1（SREBP-1）过表达介导了 DN 肾小管细胞中异常的脂质积累。然而，SREBP-1 表达增加的确切机制尚未完全阐明。本研究旨在探讨 SREBP-1 上调的机制。选择糖尿病小鼠和高糖培养的 HKCs 细胞，通过免疫组织化学、Western blot 和 PCR 检测 FBXW7 和 SREBP-1 的表达。本研究表明，FBXW7 在糖尿病小鼠肾小管细胞中的表达降低。此外，在肾小管细胞中观察到 FBXW7 和 SREBP-1 的共表达，但在肾小球中没有观察到。高糖诱导体外培养的 HKCs 细胞中 FBXW7 表达下调，同时 SREBP-1 上调。此外，在 HKCs 细胞中过表达 FBXW7 导致 SREBP-1 下调。相反，在 HKCs 细胞中敲低 FBXW7 导致 SREBP-1 上调。研究发现，PI3K/Akt 信号通路在高糖刺激的 HKCs 细胞中被激活，使用 LY294002 抑制 PI3K/Akt 通路增加了 FBXW7 的表达并降低了 SREBP-1 的表达。综上所述，本研究结果表明，FBXW7 通过 PI3K/Akt 信号通路介导了 DN 肾小管细胞中高糖诱导的 SREBP-1 表达。
