Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan, China.
FASEB J. 2024 Sep 30;38(18):e70060. doi: 10.1096/fj.202401543R.
The membrane lipid damage caused by reactive oxygen species(ROS) and various peroxides, namely lipid peroxidation, plays an important role in the progression of diabetic nephropathy (DN).We previously reported that vitamin D receptor(VDR) plays an active role in DN mice by modulating autophagy disorders. However, it is unclear whether the ATP-citrate lyase (ACLY)/NF-E2-related factor-2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is associated with the reduction of lipid peroxidation by VDR in the DN model. We found that in the DN mouse model, VDR knockout significantly aggravated mitochondrial morphological damage caused by DN, increased the expression of ACLY, promoted the accumulation of ROS, lipid peroxidation products Malondialdehyde(MDA) and 4-hydroxy-2-nonenal (4-HNE),consumed the Nrf2/Keap1 system, thus increasing lipid peroxidation. However, the overexpression of VDR and intervention with the VDR agonist paricalcitol (Pari) can reduce the above damage. On the other hand, cellular experiments have shown that Pari can significantly reduce the elevated expression of ACLY and ROS induced by advanced glycation end products (AGE). However, ACLY overexpression partially eliminated the positive effects of the VDR agonist. Next, we verified the transcriptional regulation of ACLY by VDR through chromatin immunoprecipitation (ChIP)-qPCR and dual luciferase experiments. Moreover, in AGE models, knockdown of ACLY decreased lipid peroxidation and ROS production, while intervention with Nrf2 inhibitor ML385 partially weakened the protective effect of ACLY downregulation. In summary, VDR negatively regulates the expression of ACLY through transcription, thereby affecting the state of Nrf2/Keap1 system and regulating lipid peroxidation, thereby inhibiting kidney injury induced by DN.
活性氧（ROS）和各种过氧化物引起的膜脂质损伤，即脂质过氧化，在糖尿病肾病（DN）的进展中起重要作用。我们之前报道维生素 D 受体（VDR）通过调节自噬紊乱在 DN 小鼠中发挥积极作用。然而，尚不清楚 ATP-柠檬酸裂解酶（ACLY）/核因子 E2 相关因子 2（Nrf2）/Kelch 样 ECH 相关蛋白 1（Keap1）途径是否与 VDR 在 DN 模型中降低脂质过氧化有关。我们发现，在 DN 小鼠模型中，VDR 敲除显着加重了由 DN 引起的线粒体形态损伤，增加了 ACLY 的表达，促进了 ROS、脂质过氧化产物丙二醛（MDA）和 4-羟基-2-壬烯醛（4-HNE）的积累，消耗了 Nrf2/Keap1 系统，从而增加了脂质过氧化。然而，VDR 的过表达和 VDR 激动剂帕立骨化醇（Pari）的干预可以减少上述损伤。另一方面，细胞实验表明，Pari 可以显着降低由晚期糖基化终产物（AGE）诱导的 ACLY 和 ROS 的升高表达。然而，ACLY 的过表达部分消除了 VDR 激动剂的积极作用。接下来，我们通过染色质免疫沉淀（ChIP）-qPCR 和双荧光素酶实验验证了 VDR 对 ACLY 的转录调节。此外，在 AGE 模型中，ACLY 的敲低降低了脂质过氧化和 ROS 的产生，而 Nrf2 抑制剂 ML385 的干预部分削弱了 ACLY 下调的保护作用。总之，VDR 通过转录负调节 ACLY 的表达，从而影响 Nrf2/Keap1 系统的状态并调节脂质过氧化，从而抑制由 DN 引起的肾损伤。
