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Abstract: FR-PO960

Polycystin 1 (PC1) and NPHP1 Interact with Ciliary LKB1 to Regulate Inflammation, Providing New Insights into the Pathophysiology of Ciliopathy Phenotypes

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Kuehn, E. Wolfgang, University Freiburg Medical Center, Freiburg, Germany
  • Viau, Amandine, INSERM U1151 / INEM, Paris, France
  • Bienaime, Frank, INSERM U845 - Universite Paris Descartes - APHP, Paris, France
  • Lukas, Kamile, University Freiburg Medical Center, Freiburg, Germany
  • Todkar, Abhijeet, University Freiburg Medical Center, Freiburg, Germany
  • Yakulov, Toma Antonov, University Freiburg Medical Center, Freiburg, Germany
  • Hofherr, Alexis, University Freiburg Medical Center, Freiburg, Germany
  • Grahammer, Florian, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  • Kretz, Oliver, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  • Nitschke, Roland, University Freiburg, Freiburg, Germany
  • Huber, Tobias B., University Hospital Hamburg-Eppendorf, Hamburg, Germany
  • Terzi, Fabiola, INSERM, Paris, France
  • Kottgen, Michael, University Freiburg Medical Center, Freiburg, Germany
  • Boerries, Melanie, DKFZ/DKTK, Freiburg, Germany
  • Busch, Hauke, University of Lübeck, Lübeck, Germany
  • Walz, Gerd, University Freiburg Medical Center, Freiburg, Germany
Background

Peritubular inflammation and fibrosis are key aspects of the renal ciliopathies nephronophthisis (NPH) and autosomal dominant polycystic kidney disease (ADPKD). In addition, macrophages drive cyst growth in the latter. Yet, the mechanism, how mutations in NPHP or PKD genes cause inflammation, is unknown.

Methods

Biochemistry, expression screens, molecular biology, imaging, transgenic animal models, immune phenotyping.

Results

We find that loss of Lkb1 in the kidney results in an NPH phenotype. LKB1 interacts with NPHP1 and PC1 to regulate CCL2 expression through an intra-ciliary mechanism. Loss of Lkb1 or Pkd1 in the kidney leads to increased numbers of CCR2 positive mononuclear phagocytes. Simultaneous targeting of Ccl2 or the essential cilia protein Kif3a in Pkd1 mutant mice prevents CCL2 expression, macrophage expansion and leads to an ameliorated phenotype.

Conclusion

Our findings describe a novel physiological role for PC1 and NPHP1 as gatekeepers of peritubular immune cell numbers and explain how disturbance of this function results in an essential pathological process driving these entities.

Funding

  • Government Support - Non-U.S.