Kidney Week

Abstract: TH-PO406

Obesity and PKD: Mechanistic Studies Using the Pkd1RC/RC Model

Session Information

• Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Monaghan, Marie-Louise T., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Marie-Louise T. Monaghan,

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

Dustin Nguyen,

• Berger, Michael D., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Michael D. Berger,

• D'Alessandro, Angelo, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Angelo D'Alessandro,

• Cendali, Francesca Isabelle, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Francesca Isabelle Cendali,

• 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,

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

Katharina Hopp,

Background

Obesity is a covariate of more rapid kidney cyst growth in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Murine studies suggest that immune cell function and metabolic defects influence disease progression; both of which are altered in obesity. Caloric restriction (CR), in turn, slows PKD progression in mice.

Methods

Using the C57Bl/6J Pkd1 p.R3277C (Pkd1^RC/RC) mouse, we established a diet-induced obesity model of ADPKD by ad libitum feeding a high fat diet (HFD, 42% calories from fat) from 4 weeks to 7 months of age; control diet (CD, 13% calories from fat, matched composition). PKD severity, fat mass (quantitative magnetic resonance), and kidney immune- (flow cytometry) and metabolic- (LC-MS/MS) state were assessed at study end.

Results

Compared to consumption of CD, HFD caused a 1.2-fold (p<0.01) increase in body weight in males (M)/females (F) and a 2.4-fold in M (p<0.05) and 1.8-fold in F (p<0.05) increase in fat mass. Interestingly, PKD severity only significantly worsened in females on HFD vs CD not males: increased kidney weight/femur length (1.4-fold, p<0.01), cyst- (1.98-fold, p<0.01) and fibrotic- volume (2-fold, p<0.05). Kidney metabolomics revealed significant dysregulation of the kynurenine pathway, which we recently identified as key modifier of PKD progression and immunosuppression, e.g., kynurenic acid (KA) increased by 3.1-fold (F) (p<0.001) and 1.28-fold (M) in mice on HFD vs CD. Of note, CR resulted in a 3-fold reduction in KA (p<0.05) in a separate age/sex matched study of Pkd1^RC/RC mice. Correlatively, the kidney immune landscape of Pkd1^RC/RC mice on HFD significantly shifted towards immunosuppression with increased numbers of M2-like infiltrating macrophages (1.45-fold, <0.01), CD4⁺ T_Regs (1.96-fold, p<0.05), and T cell PD-1 expression (1.8-fold, <0.01).

Conclusion

We established a model of ADPKD that mimics clinical findings of patients with ADPKD and high adiposity, although the sex dimorphism needs further investigation. We also outline kynurenines/immunosuppression as a potential mechanistic link. The model will allow evaluation of novel therapeutic/nutritional avenues to reduce adiposity and slow PKD progression as well as adiposity-linked mechanisms driving kidney cyst growth.