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Abstract: TH-PO741

Deletion of Neph1: Important for Renal Filtration but Critically Decisive for Patterning of the Enteric Nervous System

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Dumoulin, Bernhard, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Khbouz, Badr, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Grahammer, Florian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
Background

The immunoglobulin superfamily (IgSF) is a diverse group of proteins defined by the presence of one or more immunoglobulin domains. Nephrin (NPHS1) and Neph1 (NEPH1) are two well-known members of the IgSF in the kidney. They are expressed on podocytes where they form the slit diaphragm through homophilic interactions between neighboring foot processes. While many reported mutations for NPHS1 cause early-onset albuminuria leading to kidney failure, only two NEPH1 mutations have been reported, resulting in later-onset albuminuria progressing to chronic kidney disease. Knockout (ko) models for Nphs1 and Neph1 both show albuminuria and perinatal death. However, it is unclear whether death is caused by the kidney phenotype. Nephrin is expressed in podocytes, pancreas, and cerebellum, while Neph1 has a broader expression in podocytes, lung, brain, heart, skeletal muscle, liver, pancreas, and gut.

Methods

Podocyte specific conditional ko of Nphs1 and Neph1, constitutive ko of Nphs1 and Neph1, expression analysis using in-situ hybridization. Perinatal mice underwent µMRI analysis and examination of the olfactory bulb (OB) and enteric nervous system using immunofluorescence (IF) and 3D reconstruction.

Results

By utilizing podocyte specific conditional ko models of Nphs1 and Neph1, we can demonstrate that while Nphs1Pod mice die perinatally, Neph1Pod mice are viable with a median survival of 4.5 months, indicating that the kidney phenotype is not the cause of perinatal death. We found increased expression of Neph1 in the OB of mouse embryos. Shortly after birth, we found Neph1 at the axon terminals of primary olfactory sensory cells in the ventromedial zone of the OB. We used olfactory marker protein (OMP) as an indirect marker for disturbed axonal guiding and found a condensed layer of OMP with insufficient transport to the specific glomeruli in Neph1-/- mice. Furthermore, µMRI of perinatal Neph1-/- mice revealed widened, fluid filled bowels. Using IF, we found a much wider ganglion network of the enteric nervous system in ileum and colon of Neph1-/- mice, suggesting a disturbed regulation of peristalsis.

Conclusion

We believe, this offers a plausible rationale for the perinatal mortality observed in Neph1-/- mice, as well as the low occurrence and hypomorphic characteristics of NEPH1 variants found so far in humans.

Funding

  • Government Support – Non-U.S.