Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study

International Journal of Molecular Sciences

Yuh-Feng Lin¹  Mai-Szu Wu¹  Jhih-Cheng Wang²  Yen-Chung Lin³  Kuan-Chou Chen³  Chiung-Chi Peng³  Chang-Rong Chen⁴  Chang-Yu Chen⁵ 

[1] Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan City 71004, Taiwan;Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;International Medical Doctor Program, Vita-Salute San Raffaele University, 20132 Milan, Italy;Program of Biomedical Sciences, College of Arts and Sciences, California Baptist University, Riverside, CA 92504, USA;

关键词: chronic kidney disease;    calcium channel blocker;    lipid;    SREBP;    CD36;   

DOI  :  10.3390/ijms21124359

来源: DOAJ

【 摘 要 】

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 (p < 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 (p < 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.

【 授权许可】

Unknown