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bioRxiv · 10.1101/487264

Nifedipine Modulated Renal Lipogenesis via AMPK-SREBP Transcriptional Pathways

Lin, Y.-C.·Wu, M.-S.·Chen, C.-R.·Chen, C.-Y.·Chen, C.-J.·Chen, K.-C.·Peng, C.-C.
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Abstract

Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity occurring in the kidney can be a surrogate marker for renal failure or renal fibrosis. Nifedipine-induced renal lipotoxicity has never been cited, although a few studies have shown that nifedipine inhibits lipogenesis via activation of the LKB1-AMPK pathway. Therefore, we utilized NRK52E cell models to examine this further. We pre-treated cells with varying concentrations of nifedipine (7.5, 15, or 30 M) for 24 or 48 h prior to examining the activity of lipogenesis enzymes and lipotoxicity.\n\nNifedipine was found to activate acetyl CoA synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and HMG CoA reductase, suggesting elevated production of cholesterol, triacylglycerides, 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 transcription of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage.\n\nIn the present study, we elucidated the mechanism of action of nifedipine that leads to renal lipotoxicity via the AMPK-SREBP-1/2 pathway. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.

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Lin, Y.-C., Wu, M.-S., Chen, C.-R., Chen, C.-Y., Chen, C.-J., Chen, K.-C., Peng, C.-C.. 2018-12-04. Nifedipine Modulated Renal Lipogenesis via AMPK-SREBP Transcriptional Pathways. https://doi.org/10.1101/487264

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