Abstract
Abstract Background and Aims Tenofovir disoproxil fumarate (TDF), a reverse transcriptase inhibitor used to treat virus infections, could cause proximal tubular (PT) dysfunctions and eGFR decline with mitochondria damages. PDZ domain containing 1 (PDZK1), PDZK1-interacting protein 1 (PDZK1IP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1) are scaffold proteins or membrane-associated proteins that influence the localization and function of membrane proteins. We tried to investigate the changes of both proximal tubular transporters and membrane-associated proteins in TDF induced nephrotoxic model. Method C57/BL6 mice (n = 8) were gavaged daily with 10mg/kg/d, 50mg/kg/d of TDF for 8 weeks. The human renal tubular epithelial cells (HK-2) were grown and received 24 to 72 h exposure to 0–128 µM TDF or vehicle. Results Chronic TDF administration to mice and HK-2 cells resulted in PT damages including swollen and exfoliated tubular epithelial cells, brush border cilia lodging and dissolving, and serum creatinine elevation (P<0.05, mean 10.23±2.683 vs. 27.18±18.41) compared to the control group. The Na+/Pi cotransporter (Npt) and sodium-glucose cotransporter type 2 (SGLT-2) were decreased in the kidneys of TDF treated mice and HK-2 cells. The intracellular phosphorus concentrations decreased with the increase of TDF concentration and the extension of TDF treatment time, which were in line with down-regulated Npt expressions. Mitochondrial morphological changes were seen in TDF treated mice and HK-2 cells by electron microscope, including unclear boundaries, damaged membrane structures, disappeared mitochondrial cristae, and fragmented mitochondria or abnormal giant mitochondria in PT cells. The expression of cytochrome b was reduced by 52.0% (P<0.0001), indicating the damages of mitochondrial respiratory chain. ATP levels which reflected mitochondrial functions were also decreased after TDF treatment in HK-2 cells with a time- and dose-dependent relationship. Conclusion TDF may down-regulate Npt expression, leading to decreased intracellular phosphorus concentrations, mitochondrial dysfunctions, and finally kidney injury.
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