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Kidney Week

Abstract: PO0247

Inhibition of Acetyl-CoA Carboxylase in Acutely Injured Tubular Cells Exacerbates DNA Damage and Mitochondria Fission in Diabetic Nephropathy

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Liu, Xiangchun, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Li, Jiahua, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Cheng, Shun-Yang, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Li, Guixia, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Both diabetes and acute tubular injury (ATI) alter lipid metabolism of proximal tubules. Inhibiting lipogenesis causes G2/M cell cycle arrest, which can cause maladaptive tubular repair. Acetyl-CoA carboxylase (ACC) stimulates lipogenesis and inhibits fatty acid oxidation (FAO). Phosphorylation (p-ACC) inhibits ACC, which inhibits lipogenesis and promotes FAO. We hypothesized that p-ACC exacerbates DNA damage and mitochondria dysfunction in diabetic nephropathy (DN) after ATI.

Methods

Human DN samples were co-stained for p-ACC, KIM-1, and a-SMA. ATI was introduced by a single diphtheria toxin (DT) injection in Akita mice in which the DT receptor (DTR) was introduced genetically into the kidney tubule (AkitaSIX2-DTR). Mice were fed a high-fat diet (HFD). The expression ratio of p-ACC/ACC was determined at 3 days after DT and markers for tubular injury and DNA damage (g-H2AX) were evaluated at 3 days and 4 months. Cisplatin-injured HK2 cells were treated with an ACC inhibitor, PF-05175157 (ACCi) or a carnitine palmitoyltransferase 1 inhibitor, etomoxir (CPT1i) and examined for DNA damage and mitochondria fission.

Results

P-ACC expression was increased and correlated with expression of tubular injury marker KIM-1 and myofibroblast marker a-SMA in human DN specimens. At day 3 after DT, ATI increased the p-ACC/ACC ratio in the Akita SIX2-DTR mice on HFD and resulted in enhanced expression of g-H2AX in KIM-1 positive tubules and kidney fibrosis at 4 months. When cisplatin-injured HK2 cells were treated with ACCi, which allowed b-oxidation of acyl-CoA, there was an increase in mitochondrial fission factor (MFF) without a further increase of g-H2AX. Etomoxir, which blocked acylcarnitine entry into mitochondria, reduced MFF and g-H2AX expression.

Conclusion

Increased levels of p-ACC were associated with increased tubular injury and fibrosis in human DN. P-ACC in injured renal epithelial cells permitted b-oxidation of acyl-CoA in damaged mitochondria and enhanced mitochondrial fission resulting in DNA damage plausibly from reactive oxygen species. Prevention of mitochondrial overload of acyl-CoA is a potential therapeutic target to mitigate mitochondria damage and DNA damage after ATI in DN.

Funding

  • NIDDK Support