Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan.
Int J Mol Sci. 2020 Jun 19;21(12):4359. doi: 10.3390/ijms21124359.
Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by inhibiting the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague-Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups ( < 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys ( < 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.
脂肪酸氧化失调和脂肪酸积累可导致肾脏损伤。硝苯地平通过抑制体外近端肾小管细胞中腺苷酸 5'-单磷酸（AMP）激活的蛋白激酶（AMPK）通路来调节脂肪生成相关转录因子 SREBP-1/2。然而，硝苯地平（NF）在体内调节脂毒性的机制尚不清楚。在此，我们在阿霉素（DR）诱导的肾损伤大鼠模型中研究了 NF 的作用。将 24 只 Sprague-Dawley 大鼠分为对照组、DR 组、DR+NF 组和高脂饮食（HFD）组。DR、DR+NF 和 HFD 组出现高血压和蛋白尿。Western blot 和免疫组化分析表明，与其他组相比，NF 显著诱导 TNF-α、CD36、SREBP-1/2 和乙酰辅酶 A 羧化酶的表达和肾纤维化，并降低脂肪酸合成酶和 AMPK（<0.05）。此外，还纳入了 18 名接受肾移植的慢性肾脏病（CKD）患者，通过瞬时弹性成像检查其移植物纤维化和脂质含量。CKD 患者的低密度脂蛋白水平与移植物肾脏中的脂质含量和纤维化强烈相关（<0.05）。因此，NF 可能通过 SREBP-1/2/AMPK 通路和 CD36 上调引发脂肪生成，并增加体内肾纤维化。较高的低密度脂蛋白水平可能与 CKD 患者移植物肾脏的纤维化和脂质积累相关。
