Nifedipine Modulates Renal Lipogenesis via the AMPK-SREBP Transcriptional Pathway.

Yen-Chung Lin,Chang-Rong Chen,Chang-Jui Chen,Yuh-Feng Lin,Mai-Szu Wu,Kuan-Chou Chen,Chang-Yu Chen,Che-Chou Shen,Chiung-Chi Peng

doi:10.3390/ijms20071570

Abstract

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.

Highlights

Ectopic lipid deposition in non-adipose tissues such as the kidney may elicit organ damage with subsequent lipotoxicity, further affecting the function of the involved organs [1]
In this study, using the normal rat proximal tubular epithelial cell line NRK52E as the model, we investigated whether the lipogenesis of nifedipine is associated with the AMPK-sterol regulatory element-binding proteins (SREBPs)-lipin 1 pathway
The cell viability was further suppressed to 24.4% and 47.2% relative to the control after 48 h, compared with 42.3% caused by oleic acid (p < 0.05) (Figure 1a)

Summary

Introduction

Ectopic lipid deposition in non-adipose tissues such as the kidney may elicit organ damage with subsequent lipotoxicity, further affecting the function of the involved organs [1]. Overproduction of free fatty acids (FFA) may enhance the translocation of FFA into mitochondria, triggering the production of reactive oxygen species (ROS) in the early phase of accumulation. This results in increased mitochondrial proton conductance and uncoupling of oxidative phosphorylation, eventually provoking mitochondrial permeabilization [2], which underlies dysfunction in fatty acid oxidation (FAO). The endothelial cells undergo apoptosis, inducing inflammation and mesangial cell proliferation and eventual glomerulopathy. The tubular cells undergo apoptosis with increased autophagy vesicles, leading to interstitial inflammation and fibrosis [4]

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Results

Discussion

Conclusion