Kidney Week

Abstract: PO1556

Dietary Protein Load Increases Kidney Macrophage and Accelerates Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Huang, Jifeng, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, United States

Jifeng Huang,

• Hsu, Jung-Shan, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, United States

Jung-Shan Hsu,

• Saigusa, Takamitsu, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, United States

Takamitsu Saigusa,

Background

The disease severity for autosomal dominant polycystic kidney disease (PKD) is highly variable even among families with the same gene mutation, suggesting factors other than genetics may affect cystogenesis. One factor that accelerates cyst growth in PKD mouse is compensatory renal hypertrophy triggered by unilateral nephrectomy or a high protein diet. We recently reported that unilateral nephrectomy increases kidney macrophages, cytokines and accelerates cystogenesis in Pkd1-knockout mice. We hypothesize that Pkd1-knockout mice fed a high protein diet, similarly increases kidney macrophages and accelerates cyst growth.

Methods

We used adult tamoxifen inducible Pkd1^flox/flox mice with or without CAGG-cre. After cre induction, mice were fed either a high protein (HP: 60%), a normal protein (NP: 18%) or a low protein (LP: 6%) diet for a total of 1 or 6 weeks. Some mice fed a HP diet were treated with liposomal clodronate (to deplete macrophage) or phosphate buffer saline (intraperitoneally twice a week) for a total of 6 weeks. Mice were euthanized at the end of the experiment for kidney histology, measurements of cytokine and macrophages by FACS.

Results

Pkd1-knockout mice fed a HP diet for 6 weeks resulted in increased number of kidney resident macrophage (CD11b^lo, F4/80 ^hi) and infiltrating macrophages (CD11b^hi, F4/80^lo) compared to Pkd1-knockout mice fed a NP or LP diet. HP diet fed mice resulted in increased kidney pro-inflammatory cytokines, chemokines and severe kidney cysts growth compared to NP or LP diet fed mice. Early after dietary protein modification (1 week), Pkd1-knockout mice fed a HP diet had larger kidneys, higher cystic index and kidney mTOR level compared to LP diet fed Pkd1-knockout mice but there were no differences in the number of macrophages, chemokine and cytokine levels in the kidney. HP diet fed Pkd1-knockout mice treated with liposomal clodronate, resulted in decreased number of macrophages, cytokine and fewer cysts compared to PBS treated Pkd1-knockout mice.

Conclusion

Dietary protein load increases kidney macrophages, inflammatory cytokine production and accelerates cyst growth in adult Pkd1-knockout mice. HP diet stimulates kidney cyst expansion prior to the recruitment of macrophages early on, but subsequent macrophage depletion therapy slowed the acceleration of cyst growth.

Funding

• NIDDK Support