title: Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity.
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.
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Lan
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Song
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Cheng
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.|Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Wenna
authors.initials: W
authors.lastname: Chi
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Technology Center for Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Xu
authors.affiliation: Technology Center for Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, Denver-Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Siegenthaler
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.|Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D063065:Organophosphonates / Q000009:adverse effects*; D020543:Proteome; D040901:Proteomics; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000068698:Tenofovir / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D018841:HSP90 Heat-Shock Proteins; D063065:Organophosphonates; D020543:Proteome; C491545:SDHD protein, human; C092306:TRAP1 protein, human; C053001:adefovir; D000068698:Tenofovir; D013385:Succinate Dehydrogenase; D005947:Glucose; D000225:Adenine