NHERF1 loss upregulates enzymes of the pentose phosphate pathway in kidney cortex

Adrienne Bushau-Sprinkle, Michelle T. Barati, Kenneth B. Gagnon, Syed Jalal Khundmiri, Kathleen Kitterman, Bradford G. Hill, Amanda Sherwood, Michael Merchant, Shesh N. Rai, Sudhir Srivastava, Barbara Clark, Leah Siskind, Michael Brier, Jessica Hata, Eleanor Lederer

Research output: Contribution to journalArticle

Abstract

(1) Background: We previously showed Na/H exchange regulatory factor 1 (NHERF1) loss resulted in increased susceptibility to cisplatin nephrotoxicity. NHERF1-deficient cultured proximal tubule cells and proximal tubules from NHERF1 knockout (KO) mice exhibit altered mitochondrial protein expression and poor survival. We hypothesized that NHERF1 loss results in changes in metabolic pathways and/or mitochondrial dysfunction, leading to increased sensitivity to cisplatin nephrotoxicity. (2) Methods: Two to 4-month-old male wildtype (WT) and KO mice were treated with vehicle or cisplatin (20 mg/kg dose IP). After 72 h, kidney cortex homogenates were utilized for metabolic enzyme activities. Non-treated kidneys were used to isolate mitochondria for mitochondrial respiration via the Seahorse XF24 analyzer. Non-treated kidneys were also used for LC-MS analysis to evaluate kidney ATP abundance, and electron microscopy (EM) was utilized to evaluate mitochondrial morphology and number. (3) Results: KO mouse kidneys exhibit significant increases in malic enzyme and glucose-6 phosphate dehydrogenase activity under baseline conditions but in no other gluconeogenic or glycolytic enzymes. NHERF1 loss does not decrease kidney ATP content. Mitochondrial morphology, number, and area appeared normal. Isolated mitochondria function was similar between WT and KO. Conclusions: KO kidneys experience a shift in metabolism to the pentose phosphate pathway, which may sensitize them to the oxidative stress imposed by cisplatin.

Original languageEnglish (US)
Article number862
Pages (from-to)1-19
Number of pages19
JournalAntioxidants
Volume9
Issue number9
DOIs
StatePublished - Sep 2020

Keywords

  • Cellular redox state
  • Cisplatin nephrotoxicity
  • Mitochondrial function
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Bushau-Sprinkle, A., Barati, M. T., Gagnon, K. B., Khundmiri, S. J., Kitterman, K., Hill, B. G., Sherwood, A., Merchant, M., Rai, S. N., Srivastava, S., Clark, B., Siskind, L., Brier, M., Hata, J., & Lederer, E. (2020). NHERF1 loss upregulates enzymes of the pentose phosphate pathway in kidney cortex. Antioxidants, 9(9), 1-19. [862]. https://doi.org/10.3390/antiox9090862