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Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity
Xinbin Zhao1, Kun Sun1, Zhou Lan1, Wenxin Song1, Lili Cheng1, Wenna Chi1,2, Jing Chen1,
Yi Huo3, Lina Xu4, Xiaohui Liu4, Haiteng Deng3, Julie A. Siegenthaler5 & Ligong Chen1,2
1School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. 2Collaborative Innovation Center
for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical
School, Sichuan University, Chengdu, 610041, China.
3MOE Key Laboratory of Bioinformatics, School of Life
Sciences, Tsinghua University, Beijing, 100084, China.
4Technology Center for Protein Sciences, School of Life
Sciences, Tsinghua University, Beijing, 100084, China.
5Department of Pediatrics, Denver-Anschutz Medical Campus,
University of Colorado, Aurora, CO 80045, USA. Corres
Scientific Reports 7, Article number: 46344 (2017)
doi:10.1038/srep46344
Download Citation
Protein–protein interaction networksToxicology
Received:
14 October 2016
Accepted:
16 March 2017
Published online:
11 April 2017
Abstract
Despite the therapeutic success of tenofovir (TFV) for treatment of HIV-1 infection, numerous cases of nephrotoxicity have been reported. Mitochondrial toxicity has been purported as the major target of TFV-associated renal tubulopathy but the underlying molecular mechanism remains unclear. In this report, we use metabolomics and proteomics with HK-2 cells and animal models to dissect the molecular pathways underlying nephropathy caused by TFV and its more toxic analog, adefovir (ADV). Proteomic analysis shows that mitochondrial chaperone TRAP1 and mtDNA replicating protein SSBP1 were significantly down-regulated in TFV and ADV treated HK-2 cells compared with controls. Transmission electron microscopy (TEM) revealed that TFV and ADV-treated HK-2 cells had accumulated glycogen, a phenotype that was also observed in mice treated with TFV and ADV. Analysis of the proteins in TCA cycle showed succinate dehydrogenase subunit B (SDHB) was nearly depleted in glucose oxidative phosphorylation pathway however certain enzymes in the glycolysis and glycogen synthesis pathway had elevated expression in TFV and ADV-treated HK-2 cells. These results suggest that TFV and ADV may cause mitochondrial dysfunction in renal tubular cells and reprogramming of glucose metabolism. The resulting glycogen accumulation may partially contribute to TFV and ADV induced renal dysfunction.
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发表于 2017-4-18 21:15
