Kidney Week

Abstract: FR-PO0071

Towards a Better Understanding of NPHP3-Related Ciliopathies

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Martin, Joran, Institut Imagine, INSERM U1163, Paris, France

Joran Martin, PhD

• Rocha, Guillaume, Institut Imagine, INSERM U1163, Paris, France

Guillaume Rocha

• Cassina, Laura, Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS, San Raffaele Scientific Institute, Milan, Italy

Laura Cassina, PhD

• Consolato, Francesco, Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS, San Raffaele Scientific Institute, Milan, Italy

Francesco Consolato, PhD

• D'Anna, Melissa, Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS, San Raffaele Scientific Institute, Milan, Italy

Melissa D'Anna, MSc

• Tolockovs, Nikita, Institut Imagine, INSERM U1163, Paris, France

Nikita Tolockovs, MSc

• Jacquemin, Patrick, 3. Université catholique de Louvain, de Duve Institute, Brussels, Belgium

Patrick Jacquemin

• Saunier, Sophie, Institut Imagine, INSERM U1163, Paris, France

Sophie Saunier, PhD

• Boletta, Alessandra, Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS, San Raffaele Scientific Institute, Milan, Italy

Alessandra Boletta, PhD

• Benmerah, Alexandre, Institut Imagine, INSERM U1163, Paris, France

Alexandre Benmerah, PhD

• Viau, Amandine, Institut Imagine, INSERM U1163, Paris, France

Amandine Viau, PhD

Background

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy, emerging as the leading monogenic cause of kidney failure (KF) in children. Based on the age of onset of KF, NPH is classified into three forms. Juvenile and adolescent forms share similarities with tubular atrophy and/or dilatations, immune cell infiltration, and severe interstitial fibrosis. Unlike these forms, infantile NPH presented enlarged kidneys with cortical cysts and interstitial fibrosis. More than 25 NPHP genes have been associated with NPH, resulting in a large genetic heterogeneity with overlapping clinical phenotypes. NPHP proteins form different complexes that localize to the primary cilium. NPHP3 is the 4^th most frequent gene mutated in NPH and encode a key component of the inversin compartment. Depending on the type of NPHP3 mutations, the kidney features can vary from an infantile form to adolescent form associated. How disruption of NPHP complexes leads to the various forms of NPH remains poorly defined.

Methods

A mouse model harbouring kidney tubule-specific Nphp3 inactivation and Nphp3-deficient kidney tubular cells (mIMCD3) were generated to decipher the cellular and molecular mechanisms involved upon Nphp3 invalidation. These two models were analyzed using transcriptomic and metabolomic approaches.

Results

Loss of Nphp3 led to kidney enlargement with early formation and expansion of tubular cysts, immune cell infiltration and interstitial fibrosis associated with KF and death at 4 weeks of age, all recapitulating the phenotype observed in the infantile NPH patients. Transcriptional profiling of Nphp3-mutant mouse kidneys at the early onset of the disease (P7) showed a profound mitochondrial energy failure with translation shutdown and proteostasis impairment. Targeted metabolomics profiling revealed an accumulation of TCA-cycle related metabolites in Nphp3-mutant kidneys compared to controls, indicating mitochondrial and glycolysis dysfunctions. Accordingly, Nphp3-deficient mIMCD3 cells showed impaired mitochondrial and glycolytic activities.

Conclusion

Tubular Nphp3 inactivation at early disease onset induced a metabolic rewiring phenotype involving Warburg-like metabolic shift, defective oxidative phosphorylation, and mitochondrial dysfunction, resembling the metabolic alterations observed in polycystic kidney disease.

Acknowledgment

We thank the members of the LEAT, histology, genomics, bioinformatics, cell imaging and image analysis facilities (S.F.R Necker INSERM US24, Paris, France) and of the mouse renal physiology facility (Cordeliers Research Center, Paris, France) for technical assistance.
We thank florine Chereau (Institut Imagine, INSERM U1163, Paris, France) and Younes Achouri (Université catholique de Louvain, de Duve Institute, Brussels, Belgium) for technical assistance.

Funding

• Government Support – Non-U.S.