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Abstract: SA-PO739

Transcriptomic Analysis of Homozygous CLVS1 H310Y Podocytes Reveals Mechanisms Driving Disease and Corticosteroid Mediated Rescue

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Lane, Brandon M., Duke University School of Medicine, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke University School of Medicine, Durham, North Carolina, United States
  • Wu, Guanghong, Duke University School of Medicine, Durham, North Carolina, United States
  • Huggins, Kinsie, Duke University, Durham, North Carolina, United States
  • Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States
Background

We have previously shown that the homozygous CLVS1 H310Y variant is a cause of familial steroid sensitive nephrotic syndrome (SSNS). This variant causes defects in clathrin mediated endocytosis that results in increased generation of reactive oxygen species and decreased viability in conditionally immortalized podocytes. These phenotypes were ameliorated by corticosteroid treatment, mimicking the phenotype in the affected family, however the exact mechanisms involved were unclear.

Methods

To identify mechanisms of disease and therapy response, we performed unbiased RNA-seq transcriptomic analysis on conditionally immortalized podocytes with WT CLVS1, homozygous CLVS1 H310Y podocytes, and corticosteroid treated homozygous H310Y podocytes (N=3 each).

Results

Among the most significant pathways disrupted by the CLVS1 H310Y variant according to Gene Ontology (GO) analysis is response to virus (p=1.26E-6). Interestingly, other top downregulated pathways including focal adhesion, cell substrate adhesion, actin cytoskeleton regulation, and cell-cell adhesion in H310Y podocytes (p=4.51E-11, 4.34E-11, 2.73E-05, and 0.000395) were also among the most significantly upregulated pathways by corticosteroid treatment (p=7.84E-23, 7.87E-23, 1.26E-05, and 0.001755). Additionally, corticosteroid treatment increased intracellular vesicle transport of proteins to the cell membrane, endoplasmic reticulum, and within mitochondria (p=6.54E-24, 7.92E-23, and 2.54E-05).

Conclusion

The results of this study identified disruption of podocyte adhesion and cytoskeletal regulation pathways in podocytes homozygous for the CLVS1 H310Y mutation. Our findings also revealed that glucocorticoid treatments partially correct the dysregulation in these pathways. Corticosteroid treatment also increased expression of vesicle transport processes that could counteract a loss in clathrin mediated endocytosis. Taken together, this data provides valuable insight into mechanisms driving disease and corticosteroid response in SSNS due to defects in CLVS1 gene and highlights pathways that may be potential therapeutic targets.

Funding

  • NIDDK Support