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Abstract: FR-PO370

ERRα Acts as a Bridge of Mitochondria and Sodium Homeostasis in Proximal Tubular Epithelial Cells Under Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Hu, Hongtu, Wuhan University Renmin Hospital, Wuhan, Hubei, China
  • Ding, Guohua, Wuhan University Renmin Hospital, Wuhan, Hubei, China
  • Liang, Wei, Wuhan University Renmin Hospital, Wuhan, Hubei, China
Background

The mechanism of sodium homeostasis in diabetic kidney disease (DKD) is unclear. In previous study, we found that the expression of sodium translocation channels (ATP1A1) and the estrogen-related receptor alpha (ERRα) were decreased only in DKD renal biopsy samples. The present study aims to investigate how ERRα involves in the regulation of mitochondrial loss and sodium homeostasis in proximal tubular epithelial cells (PTEC) under diabetes condition.

Methods

ERRα and ATP1A1 proximal tubule-specific overexpression mice (ERRαptKI, ATP1A1ptKI) were constructed and fed with high salt (4% NaCl) or normal diet (0.8%) for 4 weeks. Sodium concentration from isolated PTEC was quantified by ionophore ICPMS analysis. The changes of renal injury markers, proximal tubular sodium-related transport channels were evaluated. In vitro study,HK-2 cells were treated with high glucose (30 mM), high salt (40 mM), and high glucose + high salt for 24 h after overexpression of ERRα and ATP1A1 using adenovirus. Sodium concentration in PTEC was observed by cellular sodium fluorescence probe, morphological changes in mitochondria were observed by TEM, and CHIP-seq analysis was carried out to evaluate the transcriptional regulation of ATP1A1 by ERRα.

Results

High salt diet accelerated the pathological injury and mitochondrial damage in PTEC and provoked sodium accumulation compared with normal diet in wild type mice. STZ-treated ERRαptKI, and ATP1A1ptKI mice with high salt diet had mild pathological injury and mitochondrial damage and less sodium concentration in PTEC when compared with STZ-treated wild-type mice. In vitro study, CHIP-seq showed that ERRα regulates its transcription by binding to the promoter of ATP1A1. Sodium concentration, mitochondrial damage, and markers of kidney injury were significantly higher in HK-2 cells treated with high glucose or high salt, and further increased in the high glucose + high salt. The above changes were alleviated by overexpression of either ERRα or ATP1A1 in HK-2 cells.

Conclusion

ERRα is an exclusive nuclear transcription factor affected by diabetes in PTEC to integrate the mitochondria and sodium homeostasis via ATP1A1, sodium loading may act as a "second strike" to promote pathological injury in PTEC under diabetic condition.

Funding

  • Government Support – Non-U.S.