Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury

Hee Seong Jang, Mi Ra Noh, Eui Man Jung, Woo Yang Kim, Siddesh Southekal, Chittibabu Guda, Kirk W. Foster, David Oupicky, Fernando A. Ferrer, Babu J. Padanilam

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Regardless of the etiology, acute kidney injury involves aspects of mitochondrial dysfunction and ATP depletion. Fatty acid oxidation is the preferred energy source of the kidney and is inhibited during acute kidney injury. A pivotal role for the mitochondrial matrix protein, cyclophilin D in regulating overall cell metabolism is being unraveled. We hypothesize that mitochondrial interaction of proximal tubule cyclophilin D and the transcription factor PPARα modulate fatty acid beta-oxidation in cisplatin-induced acute kidney injury. Cisplatin injury resulted in histological and functional damage in the kidney with downregulation of fatty acid oxidation genes and increase of intrarenal lipid accumulation. However, proximal tubule-specific deletion of cyclophilin D protected the kidneys from the aforementioned effects. Mitochondrial translocation of PPARα, its binding to cyclophilin D, and sequestration led to inhibition of its nuclear translocation and transcription of PPARα-regulated fatty acid oxidation genes during cisplatin-induced acute kidney injury. Genetic or pharmacological inhibition of cyclophilin D preserved nuclear expression and transcriptional activity of PPARα and prevented the impairment of fatty acid oxidation and intracellular lipid accumulation. Docking analysis identified potential binding sites between PPARα and cyclophilin D. Thus, our results indicate that proximal tubule cyclophilin D elicits impaired mitochondrial fatty acid oxidation via mitochondrial interaction between cyclophilin D and PPARα. Hence, targeting their interaction may be a potential therapeutic strategy to prevent energy depletion, lipotoxicity and cell death in cisplatin-induced acute kidney injury.

Original languageEnglish (US)
Pages (from-to)327-339
Number of pages13
JournalKidney International
Volume97
Issue number2
DOIs
StatePublished - Feb 2020

Keywords

  • ATP depletion
  • acute kidney injury
  • chemotherapy
  • cisplatin nephrotoxicity
  • mitochondria
  • proximal tubule

ASJC Scopus subject areas

  • Nephrology

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