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

Xiao, Jing; Zhang, Xiaoli; Fu, Chensheng; Yang, Qingmei; Xie, Yufeng; Zhang, Zhenxing; Ye, Zhibin

doi:10.1038/emm.2017.287

Cited by 42 publications

(35 citation statements)

References 54 publications

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“…However, it is possible that the H + , K + -ATPase α subunit is essential in other organs under more strenuous physiological conditions. For example, impairment of this protein in the renal proximal tubule is known to contribute to hyperuricemia-induced renal tubular injury [22].…”

Section: Discussionmentioning

confidence: 99%

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Liu

Yuan

et al. 2020

Bioscience Reports

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Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a−/−) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a−/− mice were produced by gene targeting. Wild-type (WT) and Atp4a−/− mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a−/− mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a−/− mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a−/− mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a−/− mice compared with the WT mice (P<0.05). The H+, K+-ATPase α subunit is required for acid-secretory activity of parietal cells in vivo, the normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes. Chronic achlorhydria and hypergastrinemia in aged Atp4a−/− mice produced progressive hyperplasia and mucolytic and IM, and activated the Warburg effect via PI3K/AKT/mTOR signaling.

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Section: Discussionmentioning

confidence: 99%

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Liu

Yuan

et al. 2020

Bioscience Reports

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“…So far what we know is that the excretion of urinary sodium and potassium is positively related to hypertension [12,13]. In the previous basic study, we found that uric acid plays a down-regulated function in the NKA activity and its α1 subunit subcellular expression as well as the descending of the intracellular ATP, cell injury and the further activation of Src, NLRP3 and IL-1β [7]. Further, dysfunctional NKA caused by defected membrane of renal tubular cells result in diminished Na + reabsorption and urinary concentration ability [14].…”

Section: Discussionmentioning

confidence: 93%

“…In fact, the driving force of urate transporters in renal tubules comes from its basolateral Na + -K + -ATPase too. Furthermore, the NKA/Src complex has been shown to be activated in the kidney to address excess salt, and the tradeoff could be the development of salt-induced hypertension [7].…”

Section: Introductionmentioning

confidence: 99%

The association of urinary uric acid excretion with ambulatory blood pressure values in patients with chronic kidney disease

Zhou

Zheng

et al. 2020

Clin Hypertens

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Background: To analyze the association between hypertension and urinary uric acid excretion in patients with chronic kidney disease (CKD). Methods: We screened 87 patients who had been admitted at the Dept of Nephrology, Huadong hospital between April 2017 to April 2019 who had completed 24-h ambulatory blood pressure monitoring and retained 24-h urine biochemical test specimens, thirty adult patients (age ≤ 65 years) with CKD 1-2 stages were recruited in the study. Pearson's correlation analysis and multiple linear regression analysis were used to study the correlation of urinary uric acid excretion with ambulatory blood pressure values and the association of morning mean diastolic pressure (mMDP), night mean diastolic pressure (nMDP) and CV of dMSP (coefficient of variation of day mean systolic pressure) with fractional excretion of uric acid (FEua) and uric acid clearance rate (Cur). Independent T test was used to compare the differences of blood pressure values in FEua1 (FEua< 6.0%) and FEua2 (FEua≥6.0%) or Cur1 (Cur < 6.2 ml/min/1.73 m 2 ) and Cur2 (Cur ≥ 6.2 ml/min/1.73m 2 ) groups according to the median of FEua or Cur, respectively. Results: After adjusting for confounding factors, multiple linear regression analysis showed that FEua was positively associated with the mMDP and nMDP, Cur was positively associated with CV of dMSP. Levels of mMDP and nMDP in FEua1 group was lower than that in FEua2 group (both P < 0.05), level of CV of dMSP in Cur2 group were higher than that in Cur1 group (P < 0.01). Conclusions: We demonstrated that there is a positive correlation of FEua with morning and night mean diastolic pressure separately and Cur is positively related to CV of dMSP in CKD population. Monitoring the trend of urinary uric acid, may have a role in the early detection for hypertension or relative risks in the population of CKD.

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“…We have previously reported that reduction of Na/K-ATPase could significantly attenuate the Na/K-ATPase-related signaling in kidney proximal tubule cells, and potentiate the cell apoptosis [ 25 , 31 ]. A recent publication also demonstrated that impairment of Na/K-ATPase signaling may contribute to hyperuricemia-induced renal tubular injury [ 26 ]. Decrease of Na/K-ATPase is also a common phenomenon in patients with congestive heart failure [ 20 , 32 ], aging [ 33 , 34 , 35 ], diabetes with hypertension [ 36 , 37 , 38 ], and neurological disorders [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Data from clinical research showed that cardiac contractility is positively correlated with Na/K-ATPase levels in heart failure patients [ 20 , 21 ]. It was also demonstrated that signaling mediated by Na/K-ATPase α1 regulates renal and cardiac cell survival in vitro and associates with renal and cardiac function in vivo [ 22 , 23 , 24 , 25 , 26 , 27 ]. Na/K-ATPase expression can be regulated by multiple transcriptional factors and a variety of chemical compounds [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells

Fan

Ashraf

Drummond

et al. 2018

IJMS

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Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells). These variants can be detected in both cytosol and nuclear fractions. We also found that the inhibition of DNA methylation has a differential effect on the expression of ATP1A1-AS1 and its sense gene. To investigate the physiological role of this antisense gene, we overexpressed the ATP1A1-AS1 transcripts, and examined their effect on Na/K-ATPase expression and related signaling function in human kidney cells. The results showed that overexpression of the ATP1A1-AS1-203 transcript in HK2 cells reduced the Na/K-ATPase α1 (ATP1A1) gene expression by approximately 20% (p < 0.05), while reducing the Na/K-ATPase α1 protein synthesis by approximately 22% (p < 0.05). Importantly, overexpression of the antisense RNA transcript attenuated ouabain-induced Src activation in HK2 cells. It also inhibited the cell proliferation and potentiated ouabain-induced cell death. These results demonstrate that the ATP1A1-AS1 gene is a moderate negative regulator of Na/K-ATPase α1, and can modulate Na/K-ATPase-related signaling pathways in human kidney cells.

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

Cited by 42 publications

References 54 publications

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

The association of urinary uric acid excretion with ambulatory blood pressure values in patients with chronic kidney disease

Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells

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