Kidney Week

Abstract: SA-PO122

Altered Citrate Metabolism Leads to Maladaptive Repair After Tubular Injury and Facilitates Kidney Fibrosis in Diabetic Nephropathy

Session Information

• AKI: Mechanisms - AKI-CKD Transition
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Li, Jiahua, Brigham and Women's Hospital, Boston, Massachusetts, United States

Jiahua Li,

• Chang, Jae Hyung, Columbia University Medical Center, New York, New York, United States

Jae Hyung Chang,

• Suzuki, Tomohisa, Otsuka Pharmaceuticals, Naruto, TOKUSHIMA, Japan

Tomohisa Suzuki,

• Yang, Chen, Yale University School of Medicine, New Havens, Connecticut, United States

Chen Yang,

• Mori, Yutaro, Brigham and Women's Hospital, Boston, Massachusetts, United States

Yutaro Mori,

• Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States

Michifumi Yamashita,

• Sabbisetti, Venkata, Brigham and Women's Hospital, Boston, Massachusetts, United States

Venkata Sabbisetti,

• Ichimura, Takaharu, Brigham and Women's Hospital, Boston, Massachusetts, United States

Takaharu Ichimura,

• Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States

Joseph V. Bonventre,

Background

Dysregulated lipid metabolism is a primary feature of DKD. Citrate is a tricarboxylic acid cycle metabolite and a regulator of lipid metabolism via ATP-citrate lyase (ACLY) and acetyl-CoA carboxylase (ACC). Citrate accumulates in the renal parenchyma after AKI. We hypothesized that altered citrate metabolism contributes to maladaptive tubular repair after AKI and progression of diabetic nephropathy.

Methods

We generated C57B/6 Akita^DTR mice expressing the simian diphtheria toxin receptor (DTR) in the renal tubule in a non-obese diabetic background. Animals on a high-fat diet (HFD) were administered one dose of DT to induce tubular injury, and the kidney tissue damage was evaluated at four months. In a cisplatin toxicity model in vitro, LLC-PK₁ kidney epithelial cells were exposed to high glucose or high palmitic acid concentrations, and analyzed for cell cycle arrest, DNA damage response, and alteration in citrate metabolism.

Results

DT-treated Akita^DTR mice on HFD developed overt proteinuria, severe tubulointerstitial fibrosis, secondary glomerular sclerosis, interstitial inflammation, capillary rarefaction, and podocyte dropout, while the control littermates without tubular injury, or without diabetes, or without HFD did not. The Akita^DTR mice on HFD had increased inhibitory phosphorylation of ACC (p-ACC). In cisplatin-treated cells in high glucose, G2/M arrest was associated with increased citrate concentration, and compensatory decreased p-ACC and increased ACLY. Co-treatment with palmitic acid and cisplatin increased p-ACC and enhanced DNA damage and G2/M arrest. When compared with cisplatin treatment alone, co-treatment with a small molecule inhibitor of ACC and cisplatin also increased DNA damage, G2/M arrest, and the conditioned media from the kidney epithelial cells enhanced a-SMA production by 10T^1/2 pericyte-like cells.

Conclusion

Citrate-derived acetyl-CoA facilitates tubular repair. Inhibitory phosphorylation of ACC by exogenous lipid or pharmacological inhibition of ACC resulted in more DNA damage, G2/M arrest, and production of pro-fibrotic agents by renal epithelial cells after AKI.

Funding

• NIDDK Support