Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study
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. Howe...
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/12/4359 |
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| author | Yen-Chung Lin Jhih-Cheng Wang Mai-Szu Wu Yuh-Feng Lin Chang-Rong Chen Chang-Yu Chen Kuan-Chou Chen Chiung-Chi Peng |
| author_facet | Yen-Chung Lin Jhih-Cheng Wang Mai-Szu Wu Yuh-Feng Lin Chang-Rong Chen Chang-Yu Chen Kuan-Chou Chen Chiung-Chi Peng |
| author_sort | Yen-Chung Lin |
| collection | DOAJ |
| description | 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 (<i>p</i> < 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 (<i>p</i> < 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. |
| first_indexed | 2024-03-10T19:02:35Z |
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| language | English |
| last_indexed | 2024-03-10T19:02:35Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ca49bfcd506c44518a784a772e85da3e2023-11-20T04:20:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012112435910.3390/ijms21124359Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human StudyYen-Chung Lin0Jhih-Cheng Wang1Mai-Szu Wu2Yuh-Feng Lin3Chang-Rong Chen4Chang-Yu Chen5Kuan-Chou Chen6Chiung-Chi Peng7Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDivision of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan City 71004, TaiwanDivision of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDivision of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanInternational Medical Doctor Program, Vita-Salute San Raffaele University, 20132 Milan, ItalyProgram of Biomedical Sciences, College of Arts and Sciences, California Baptist University, Riverside, CA 92504, USAGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDysregulation 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 (<i>p</i> < 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 (<i>p</i> < 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.https://www.mdpi.com/1422-0067/21/12/4359chronic kidney diseasecalcium channel blockerlipidSREBPCD36 |
| spellingShingle | Yen-Chung Lin Jhih-Cheng Wang Mai-Szu Wu Yuh-Feng Lin Chang-Rong Chen Chang-Yu Chen Kuan-Chou Chen Chiung-Chi Peng 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 chronic kidney disease calcium channel blocker lipid SREBP CD36 |
| title | Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study |
| title_full | Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study |
| title_fullStr | Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study |
| title_full_unstemmed | Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study |
| title_short | Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study |
| title_sort | nifedipine exacerbates lipogenesis in the kidney via kim 1 cd36 and srebp upregulation implications from an animal model for human study |
| topic | chronic kidney disease calcium channel blocker lipid SREBP CD36 |
| url | https://www.mdpi.com/1422-0067/21/12/4359 |
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