Kidney Week

Abstract: SA-PO588

The Co-chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Session Information

• Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Neubauer, Bjoern, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Bjoern Neubauer, PhD

• Busch, Tilman, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Tilman Busch

• Schmitt, Lars, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Lars Schmitt, APN

• Westermann, Lukas, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Lukas Westermann, MD

• Hofherr, Alexis, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Alexis Hofherr

• Kottgen, Michael, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

Michael Kottgen, MD

Background

Autosomal dominant polycystic kidney disease (ADPKD) arises due to mutations in the genes PKD1 and PKD2, which encode the membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 form a receptor-ion channel complex participating in the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation from epithelial cells of all nephron segments. Mutations in genes, which encode endoplasmic reticulum (ER)-resident proteins have been previously demonstrated to cause atypical forms of ADPKD. Here, we investigate the function of DNAJB11, an ER co-chaperone, in the development of ADPKD.

Methods

Murine models with constitutive and inducible Dnajb11 inactivation as well as Dnajb11-deficient renal epithelial cells were generated to investigate the genetic mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms that lead to DNAJB11-dependent polycystic kidney disease.

Results

Through the use of mouse models with constitutive and conditional Dnajb11 inactivation, we show that homozygous loss of Dnajb11 results in polycystic kidney disease, while heterozygous animals are healthy. This suggests that cyst formation is recessive at the cellular level. The formation of cysts begins in utero and the timing of Dnajb11 inactivation significantly influences the severity of the phenotype. In contrast to classical ADPKD, cysts in Dnajb11-related kidney disease originate almost exclusively from proximal tubular cells. In addition, we identify impaired processing of Polycystin-1 as a molecular mechanism contributing to cystogenesis, but also find additional proteins that are dysregulated in Dnajb11 deficient cells.

Conclusion

We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis in mice, closely resembling human disease characteristics. These findings contribute to a better understanding of the pathogenic mechanisms of DNAJB11-related kidney disease. The observation that cysts already form in embryonic kidneys and emanate exclusively from proximal tubules has important implications since the knowledge of disease-specific time points and cell types is critical for the future development of therapeutic approaches.

Funding

• Government Support – Non-U.S.