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Impaired Na+-K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury.

ABSTRACT: 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 ?1 expression vector or small interfering RNA before UA (100??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 ?1 subunit, Src, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and interleukin 1? (IL-1?) were measured both in vitro and in vivo. Beginning at concentrations of 100??g?ml-1, UA started to dose-dependently reduce NKA activity. UA at a concentration of 100??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 ?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? processing. In hyperuricemic rats, renal cortex NKA activity and its ?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?. 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? in the renal proximal tubule contributed to hyperuricemia-induced renal tubular injury.

SUBMITTER: Xiao J

PROVIDER: S-EPMC5898891 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Impaired Na+-K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury.

Xiao Jing J Zhang Xiaoli X Fu Chensheng C Yang Qingmei Q Xie Ying Y Zhang Zhenxing Z Ye Zhibin Z

Experimental & molecular medicine 20180302 3

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 α1 expression vector or small interfering RNA before UA (100 μg ml-1, 48 h) stimulation. Hyperuricemic rats were ...[more]

PMID: 29497172

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Project description:Background: The basolateral potassium channels play an important role in maintaining the membrane transport in the renal proximal tubules (PT) and adenosine receptors have been shown to regulate the trans-epithelial Na+ absorption in the PT. The aim of the present study is to explore whether adenosine also regulates the basolateral K+ channel of the PT and to determine the adenosine receptor type and the signaling pathway which mediates the effect of adenosine on the K+ channel. Methods: We have used the single channel recording to examine the basolateral K+ channel activity in the proximal tubules of the mouse kidney. All experiments were performed in cell-attached patches. Results: Single channel recording has detected a 50 pS inwardly-rectifying K+ channel with high channel open probability and this 50 pS K+ channel is a predominant type K+ channel in the basolateral membrane of the mouse PT. Adding adenosine increased 50 pS K+ channel activity in cell-attached patches, defined by NPo (a product of channel Numbers and Open Probability). The adenosine-induced stimulation of the 50 pS K+ channel was absent in the PT pretreated with DPCPX, a selective inhibitor of adenosine A1 receptor. In contrast, adenosine was still able to stimulate the 50 pS K+ channel in the PT pretreated with CP-66713, a selective adenosine A2 receptor antagonist. This suggests that the stimulatory effect of adenosine on the 50 pS K+ channel of the PT was mediated by adenosine-A1 receptor. Moreover, the effect of adenosine on the 50 pS K+ channel was blocked in the PT pretreated with U-73122 or Calphostin C, suggesting that adenosine-induced stimulation of the 50 pS K+ channels of the PT was due to the activation of phospholipase C (PLC) and protein kinase C (PKC) pathway. In contrast, the inhibition of phospholipase A2 (PLA2) with AACOCF3 or inhibition of protein kinase A (PKA) with H8 failed to block the adenosine-induced stimulation of the 50 pS K+ channel of the PT. Conclusion: We conclude that adenosine activates the 50 pS K+ channels in the basolateral membrane of PT via adenosine-A1 receptor. Furthermore, the effect of adenosine on the 50 pS K+ channel is mediated by PLC-PKC signaling pathway.

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Impaired Na+-K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury.

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Impaired Na<sup>+</sup>-K<sup>+</sup>-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury.

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