Activation of branched chain amino acid catabolism protects against nephrotoxic acute kidney injury

Samaneh DiMartino, Monica P. Revelo, Sandeep K. Mallipattu, Sian E. Piret

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD), and there are currently no therapies for AKI. Proximal tubules (PTs) are particularly susceptible to AKI, due to nephrotoxins such as aristolochic acid I (AAI). Normal PTs use fatty acid oxidation and branched chain amino acid (BCAA; valine, leucine, and isoleucine) catabolism to generate ATP; however, in AKI, these pathways are downregulated. Our aim was to investigate the utility of a pharmacological activator of BCAA catabolism, BT2, in preventing nephrotoxic AKI. Mice were administered two injections of AAI 3 days apart to induce AKI, with or without daily BT2 treatment. Mice treated with BT2 had significantly protected kidney function (reduced serum creatinine and urea nitrogen), reduced histological injury, preservation of PT (Lotus lectin staining), and less PT injury (cytokeratin-20 staining) and inflammatory gene expression compared with mice with AAI alone. Mice with AKI had increased circulating BCAA and accumulation of BCAA in the kidney cortex. Leucine is a potent activator of the mechanistic target of rapamycin complex 1 (mTORC1) signaling, and mTORC1 signaling was activated in mice treated with AAI. However, BT2 reduced kidney cortical BCAA accumulation and attenuated the mTORC1 signaling. In vitro, injured primary PT cells had compromised mitochondrial bioenergetics, but cells treated with AAI BT2 had partially restored mitochondrial bioenergetics and improved injury markers compared with cells treated with AAI alone. Thus, pharmacological activation of BCAA catabolism using BT2 attenuated nephrotoxic AKI in mice.

Original languageEnglish
Pages (from-to)F152-F163
JournalAmerican Journal of Physiology - Renal Physiology
Volume328
Issue number1
DOIs
StatePublished - Jan 2025
Externally publishedYes

Keywords

  • acute kidney injury
  • branched chain amino acids
  • cellular metabolism
  • proximal tubule

Fingerprint

Dive into the research topics of 'Activation of branched chain amino acid catabolism protects against nephrotoxic acute kidney injury'. Together they form a unique fingerprint.

Cite this