Kidney Week

Abstract: PO2457

Mice with a Deficient Myeloid COX-2/EP4 Axis Developed More Severe Kidney Dysfunction in Response to a High-Fat Diet

Session Information

• CKD: Inflammation, Endothelial Dysfunction, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Cao, Shirong, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Shirong Cao, PhD

• Pan, Yu, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yu Pan,

• Tang, Jiaqi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jiaqi Tang,

• Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yinqiu Wang,

• Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Aolei Niu,

• Fan, Xiaofeng, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Xiaofeng Fan,

• Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Suwan Wang,

• Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ming-Zhi Zhang,

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

Background

Obesity leads to a state of chronic, low-grade inflammation that contributes to insulin resistance and type 2 diabetes as well as chronic kidney injury. Macrophages are major contributors to obesity-associated adipose inflammation and dysregulated metabolism. When fed a high fat diet (HFD), cyclooxygenase-2 (COX-2) expression increased in adipose tissue macrophages (ATMs). Mice with myeloid deletion of COX-2 or its EP4 receptors resulted in increased obesity after the HFD. The current studies investigated whether kidney dysfunction was exacerbated in mice with myeloid COX-2 or EP4 deletion fed a HFD.

Methods

αααWe developed myeloid COX-2-/- mice (CD11b-Cre; COX-2^f/f) and myeloid EP4-/- mice (CD11b-Cre; EP4^f/f). COX-2^f/fmice and EP4^f/f mice were used as corresponding WT controls. The mice were fed a HFD (36% fat accounting for 60% of calories) for 12 weeks.

Results

The HFD induced greater increases in body weight, fasting blood glucose, and plasma concentrations of insulin, free fatty acids, TNF-a, and leptin. The HFD-treated myeloid COX-2-/- mice and myeloid EP4-/- mice had albuminuria, kidney weight, and kidney weight vs. body weight ratio, compared to WT mice. Histologically, HFD-treated myeloid COX-2-/- mice and myeloid EP4-/- mice had more mesangial expansion, increased glomerular volume and lipid deposition in epithelial cells as well as increased immune cell infiltration. Flow cytometry and qPCR analysis showed increased renal macrophages and cytotoxic CD8 T cells and increased mRNA levels of renal proinflammatory cytokines such as Ccl2 and Il6 and profibrotic and fibrotic components including Col1α1, Col3α1, Col4α1, Fn, and Tgfb1.

Conclusion

These studies found that mice with myeloid cell deletion of COX-2 and EP4 are more sensitive to high fat diet-induced obesity and develop more severe kidney dysfunction and immune cell infiltration. The potential role of increased adipokines, insulin, free fatty acids, and leptin in the observed exacerbated kidney dysfunction are under investigation.

Funding

• NIDDK Support