Kidney Week

Abstract: SA-PO644

Ccr2 Targeting Does Not Ameliorate Disease Phenotype in a Model of UMOD-Related Autosomal Dominant Tubulointerstitial Kidney Disease

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Cratere, Mariapia Giuditta, Universita Vita Salute San Raffaele, Milano, Italy

Mariapia Giuditta Cratere, PhD

• Nicola, Francesca, Universita Vita Salute San Raffaele, Milano, Italy

Francesca Nicola, MSc

• Trudu, Matteo, Universita Vita Salute San Raffaele, Milano, Italy

Matteo Trudu

• Schaeffer, Celine, Universita Vita Salute San Raffaele, Milano, Italy

Celine Schaeffer, PhD

• Rampoldi, Luca, Universita Vita Salute San Raffaele, Milano, Italy

Luca Rampoldi, PhD

Group or Team Name

• Molecular Genetics of Renal Disorders Unit.

Background

Mutations in UMOD, encoding uromodulin, cause UMOD-related Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD). The common gain-of-function effect of UMOD mutations is endoplasmic reticulum (ER) retention and aggregation of mutant uromodulin. In a transgenic mouse model of the disease (Tg^UmodC147W) we detected significant upregulation of pro-inflammatory chemokines already at one day post-natal, well before any sign of kidney damage, suggesting a key role of early inflammation in disease pathogenesis. All upregulated chemokines are ligands of the C-C Motif Chemokine Receptor Ccr2, mainly expressed by circulating monocytes and important for their migration to inflamed sites. Here, we investigated the effect of targeting Ccr2-axis on ADTKD-UMOD kidney disease.

Methods

We adopted a genetic approach by generating Tg^UmodC147W/Ccr2^-/- mice that were characterized at 1 week (presymptomatic) and 24 weeks (late disease) of age and compared with both Tg^UmodC147W/Ccr2^+/+ and WT/Ccr2^+/+ mice (non-transgenic littermates).

Results

Ccr2 ablation did not affect Umod expression levels nor mutant uromodulin ER retention in kidneys of Tg^UmodC147W mice. Following extensive phenotype analysis, we did not observe decreased inflammation, fibrosis and expression of tubular damage markers at any studied timepoint in kidneys of Tg^UmodC147W/Ccr2^-/- mice compared to age-matched Tg^UmodC147W/Ccr2^+/+, demonstrating that deletion of Ccr2 receptor is not sufficient to improve phenotype of Tg^UmodC147W mice. To assess possible compensatory inflammatory pathways acting in response to loss of Ccr2 signalling, we studied Ccr1, Ccr3 and Ccr5 axes. Tg^UmodC147W/Ccr2^-/- mice showed increased expression of Ccr5 (24-weeks of age) and Ccr1 (1 and 24 weeks of age). These data suggest that Ccr2 ablation in Tg^UmodC147W mice induces compensatory activation of inflammatory pathways contributing to disease onset (Ccr1) and sustainment (Ccr5) in Tg^UmodC147W/Ccr2^-/- mice.

Conclusion

Our results demonstrate that Ccr2 targeting is not sufficient to block inflammation and prevent kidney disease progression in ADKTD-UMOD. These data provide evidence for the context-dependent redundance of Ccr receptors in triggering the inflammatory process.

Funding

• Private Foundation Support