Kidney Week

Abstract: PO1204

Dysregulated Tryptophan Metabolism Promotes Polycystic Kidney Disease Progression

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Nguyen, Dustin, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Dustin Nguyen

• Kleczko, Emily K., University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Emily K. Kleczko,

• Dwivedi, Nidhi, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Nidhi Dwivedi,

• Gitomer, Berenice Y., University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Berenice Y. Gitomer,

• Chonchol, Michel, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol,

• Nemenoff, Raphael A., University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Raphael A. Nemenoff,

• Klawitter, Jelena, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Jelena Klawitter,

• Hopp, Katharina, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States

Katharina Hopp,

Background

Metabolic reprogramming is a feature and modifier of autosomal dominant polycystic kidney disease (ADPKD) progression. Moreover, immune cells regulate cyst growth. In cancer, a disease with parallels to PKD, the metabolic landscape created by tumors significantly impacts immune cell function and tumor growth. Yet, this link is unexplored in PKD. Here, we study tryptophan metabolism, a known immunosuppressive pathway, in cyst growth.

Methods

Metabolites were profiled in ADPKD patient plasma and kidneys of an orthologous ADPKD model (C57Bl/6J Pkd1^RC/RC). We also crossed the ADPKD model to Ido1^-/- mice, the enzyme metabolizing tryptophan to kynurenines, and inhibited IDO1 using the tryptophan analog 1-MT (400mg/kg, twice daily, orally). From these mice, kidney immune cells were profiled via flow cytometry.

Results

Tryptophan metabolites were significantly increased in Pkd1^RC/RC mice at 3-, 6-, and 9-months compared to wildtype and correlated with disease progression. Plasma levels of kynurenines significantly associated with HtTKV at baseline, and positively correlated with annual percent change of HtTKV in adult ADPKD patients. IDO1 levels were significantly increased in kidneys of PKD mice and patient cell lines. At 6-months of age, Pkd1^RC/RC;Ido1^-/- mice had significantly milder PKD compared to Pkd1^RC/RC mice as measured by %KW/BW and cystic/fibrotic index. Similarly, treatment of 1-month-old Pkd1^RC/RC mice with 1-MT for 3 weeks slowed cyst growth; overall providing functional evidence of the pathway’s relevance to PKD. Kidney immune profiling of Pkd1^RC/RC;Ido1^-/- and 1-MT-treated mice revealed a significant reduction of resident macrophages, regulatory T cells, and immune checkpoint protein expression (PD-1/PD-L1), while the percentage of CD8⁺ T cells/total T cells increased.

Conclusion

Our data highlight tryptophan metabolism as a novel dysregulated pathway in murine and human ADPKD and suggest that tryptophan metabolites are biomarkers of disease progression. Further, inhibition of the pathway presents a new treatment approach. IDO1 inhibitors are FDA approved for various cancers. Our data suggest a link between metabolic reprogramming, immune cell function, and disease progression, as IDO1 loss/inhibition impacted immune cell populations/pathways shown to regulate cyst growth.

Funding

• NIDDK Support