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Hypoxia-mediated regulation of mitochondrial transcription factors in renal epithelial cells: implications for hypertensive renal physiology

Abstract

Kidneys have a high resting metabolic rate and low partial pressure of oxygen due to enhanced mitochondrial oxygen consumption and ATP production needed for active solute transport. Heightened mitochondrial activity leads to progressively increasing hypoxia from the renal cortex to the renal medulla. Renal hypoxia is prominent in hypertensive rats due to increased sodium reabsorption within the nephrons, which demands higher energy production by oxidative phosphorylation (OXPHOS). Consequently, spontaneously hypertensive rats (SHR) display greater oxygen deficiency (hypoxia) than normotensive Wistar Kyoto rats (WKY). Here, we sought to investigate the expression of key proteins for mitochondrial biogenesis in SHR and WKY, and study the regulation of mitochondrial transcription factors (mtTFs) under in vitro hypoxic conditions in renal epithelial cells. We report that renal expressions of hypoxia-inducible factor-1-alpha (HIF-1α), peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), mtTFs, and OXPHOS proteins are elevated in SHR compared to WKY. In addition, our experiments in cultured kidney cells demonstrate that acute hypoxia augments the expression of these genes. Furthermore, we show that the transcripts of HIF-1α and mtTFs are positively correlated in various human tissues. We reveal, for the first time to our knowledge, that HIF-1α transactivates mtTF genes by direct interaction with their promoters in rat kidney epithelial cells (NRK-52E) under acute hypoxia. Concomitant increases in the mitochondrial DNA and RNA, and OXPHOS proteins are observed. Taken together, this study suggests that hypoxia within the renal epithelial cells may enhance mitochondrial function to meet the energy demand in proximal tubular cells during prehypertensive stages in kidneys of young SHR.

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Acknowledgements

Various Government of India Research fellowships were received from the Council of Scientific and Industrial Research (BN), the Department of Science and Technology (VA), Ministry of Human Resource Development (AAK), and the Indian Council of Medical Research (SSR). The authors thank Manish Jain and Dr Madhu Dikshit, CSIR-Central Drug Research Institute, Lucknow, India, for their help at the initial phase of this study. The authors appreciate the valuable and timely help offered by V. Janani, Indian Institute of Technology Madras, Chennai, India.

Funding

This work was supported by a grant from the Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India, to NRM (project number EMR/2017/004250).

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Natarajan, B., Arige, V., Khan, A.A. et al. Hypoxia-mediated regulation of mitochondrial transcription factors in renal epithelial cells: implications for hypertensive renal physiology. Hypertens Res 44, 154–167 (2021). https://doi.org/10.1038/s41440-020-00539-4

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Keywords

  • hypoxia
  • mitochondrial biogenesis
  • mitochondrial transcription factors
  • renal epithelial cells
  • spontaneously hypertensive rats

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