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Kidney Week

Abstract: FR-PO153

Activation of Branched Chain Amino Acid (BCAA) Catabolism Protect Against AKI

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gholami, Samaneh, Stony Brook University, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Stony Brook University, Stony Brook, New York, United States
  • Piret, Sian, Stony Brook University, Stony Brook, New York, United States
Background

BCAA (Valine, Leucine and Isoleucine) catabolic defects are implicated to be determinates of multiple diseases, however it is poorly studied in kidney injuries. Acute kidney injury (AKI) is a major risk factor for development of renal fibrosis and chronic kidney disease (CKD) but there are currently no therapies available to slow or reverse this process. AKI particularly affects proximal tubule cells (PT) and results in fundamental alterations in cellular metabolism. We previously showed that BCAA catabolic enzymes are downregulated in mice treated with the PT-specific toxin aristolochic acid I (AAI) to induce AKI, as well as human CKD. Our aim was to determine whether pharmacological activation of BCAA catabolism using the compound BT2 attenuates AAI-induced AKI.

Methods

C57Bl/6 mice were injected with 3 mg/kg AAI to induce AKI. After evaluating the frequency and dosage of AAI to induce AKI, mice were treated with two injections of AAI three days apart plus 20 mg/kg/day BT2 or DMSO. Serum was collected for urea nitrogen and creatinine measurements, and kidneys for histology, immunofluorescence, gene expression analysis, Western blotting and measurement of BCAA concentrations.

Results

There were no functional or histological differences between controls groups treated with DMSO or BT2 at baseline. Kidney function as assessed by creatinine and BUN was significantly reduced in mice treated with AAI but improved significantly in AAI+BT2 mice. Lotus lectin staining for mature PT showed extensive loss of PT in AAI-treated mice which was significantly rescued in AAI+BT2 mice. Moreover, PT injury markers such as kidney injury molecule1 (Kim-1), vimentin (Vim) and cytokeratin 20 (KRT-20) which were induced by AAI, were also attenuated in AAI+BT2 mice. We also identified an increased BCAA accumulation in kidney cortex of mice treated with AAI compared with controls, which was attenuated in AAI+BT2 mice. Interestingly, m-TORC1 pathway showed significant increase in AAI treated mice compared to controls which may be due to leucine accumulation in PT cells, whereas phospho-mTOR was reduced in AAI+BT2 mice.

Conclusion

Pharmacological activation of BCAA catabolism attenuated AKI features in mice by improving metabolism and reducing BCAA accumulation in cells which may be toxic for PT cells.