Journal
EXPERIMENTAL AND MOLECULAR MEDICINE
Volume 50, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emm.2017.287
Keywords
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Funding
- Shanghai Municipal Commission of Health and Family Planning [20134075]
- Natural Science Foundation of Shanghai [17ZR1409100]
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Hyperuricemia contributes to renal inflammation. We aimed to investigate the role of Na+-K+-ATPase (NKA) in hyperuricemia-induced renal tubular injury. Human primary proximal tubular epithelial cells (PTECs) were incubated with uric acid (UA) at increasing doses or for increasing lengths of time. PTECs were then stimulated by pre-incubation with an NKA alpha 1 expression vector or small interfering RNA before UA (100 mu g ml(-1), 48 h) stimulation. Hyperuricemic rats were induced by gastric oxonic acid and treated with febuxostat (Feb). ATP levels, the activity of NKA and expression of its alpha 1 subunit, Src, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and interleukin 1 beta (IL-1 beta) were measured both in vitro and in vivo. Beginning at concentrations of 100 mu g ml(-1), UA started to dose-dependently reduce NKA activity. UA at a concentration of 100 mu g ml(-1) time-dependently affected the NKA activity, with the maximal increased NKA activity at 24 h, but the activity started to decrease after 48 h. This inhibitory effect of UA on NKA activity at 48 h was in addition to a decrease in NKA alpha 1 expression in the cell membrane, but an increase in lysosomes. This process also involved the subsequent activation of Src kinase and NLRP3, promoting IL-1 beta processing. In hyperuricemic rats, renal cortex NKA activity and its alpha 1 expression were upregulated at the 7th week and both decreased at the 10th week, accompanied with increased renal cortex expression of Src, NLRP3 and IL-1 beta. The UA levels were reduced and renal tubular injuries in hyperuricemic rats were alleviated in the Feb group. Our data suggested that the impairment of NKA and its consequent regulation of Src, NLRP3 and IL-1 beta in the renal proximal tubule contributed to hyperuricemia-induced renal tubular injury.
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