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Arch Toxicol. 2018 Jan;92(1):469-485. doi: 10.1007/s00204-017-2048-0. Epub 2017 Sep 4.

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity.

Author information

1
School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China.
2
School of Life Sciences, Tsinghua University, Beijing, China.
3
Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
4
Institute of Immunology, School of Medicine, Tsinghua University, Beijing, China.
5
Technology Center for Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
6
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
7
Department of Pediatrics, Denver-Anschutz Medical Campus, University of Colorado, Aurora, USA.
8
School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China. ligongchen@biomed.tsinghua.edu.cn.
9
Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China. ligongchen@biomed.tsinghua.edu.cn.

Abstract

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFβ pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 μM) as compared with those in controls. Zoledronate treatments in cells (50 μM) and mice (3 mg/kg) increased TGFβ/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid β-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.

KEYWORDS:

Fatty acid transporter; Lipid accumulation; Renal fibrosis; TGFβ1 signaling; Zoledronate

PMID:
28871336
PMCID:
PMC5773652
DOI:
10.1007/s00204-017-2048-0
[Indexed for MEDLINE]
Free PMC Article

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