TY - JOUR
T1 - Nifedipine Modulates Renal Lipogenesis via the AMPK-SREBP Transcriptional Pathway
AU - Lin, Yen Chung
AU - Wu, Mai Szu
AU - Lin, Yuh Feng
AU - Chen, Chang Rong
AU - Chen, Chang Yu
AU - Chen, Chang Jui
AU - Shen, Che Chou
AU - Chen, Kuan Chou
AU - Peng, Chiung Chi
N1 - Funding Information:
Acknowledgments: We wish to thank Robert Y. Peng for editing and reviewing the whole manuscript. We are grateful to Chin-Yuan Chung for technical assistance. This research received funding from Taipei Medical University and National Taiwan University of Science and Technology (No. TMU-NTUST-107-07). We also acknowledge funding offered by the Ministry of Science and Technology (MOST106-2320-B-038-032 and MOST105-2320-B-038-034-MY3).
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.
AB - Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.
KW - AMPK
KW - calcium channel blockers
KW - lipin-1
KW - nifedipine
KW - renal lipotoxicity
KW - sterol regulatory element-binding proteins 1/2 (SREBP1/2)
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U2 - 10.3390/ijms20071570
DO - 10.3390/ijms20071570
M3 - Article
C2 - 30934807
AN - SCOPUS:85064217365
SN - 1661-6596
VL - 20
SP - 1
EP - 15
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 7
ER -
