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Abstract: PO1697

Anillin Serves a Protective Function in a Mouse Model of HIV-Associated Nephropathy

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Lane, Brandon M., Duke University Department of Pediatrics, Durham, North Carolina, United States
  • Musick, Alexis, Duke University Department of Pathology, Durham, North Carolina, United States
  • Wu, Guanghong, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
  • Hall, Gentzon, Duke University Hospital, Durham, North Carolina, United States
  • Howell, David Noble, Duke University Department of Pathology, Durham, North Carolina, United States
  • Gbadegesin, Rasheed A., Duke University Department of Pediatrics, Durham, North Carolina, United States
Background

HIV associated nephropathy (HIVAN) is characterized by a rapid progression to end stage kidney disease with limited treatment options. We previously demonstrated that mutations in the gene encoding anillin (ANLN) can cause FSGS and showed that ANLN is upregulated in the glomerulus of HIVAN patients as well as the HIVAN Tg26 mouse model. ANLN is an F-actin binding protein that affects cell proliferation and survival, two cell processes that are predicted to play a key role in the phenotype associated with HIVAN. We hypothesized that ANLN upregulation is one of the drivers of glomerular disease in HIVAN mice, therefore modulating ANLN expression may present an alternative therapeutic strategy for HIVAN.

Methods

To evaluate the therapeutic potential of reduced functional ANLN in a HIVAN mouse model, we created a mouse line using CRISPR Cas9 mediated gene editing that contains an early stop codon in the Anln gene (ANLNx). We then bred heterozygous ANLNx mice with Tg26 HIVAN mice and evaluated proteinuria and mortality over 16 weeks for each genotype. Sclerotic glomeruli from 3 mice in each group were evaluated and quantified at 16 weeks of age by pathologists blinded to genotype.

Results

There was no improvement in glomerular disease phenotype associated with the reduction of functional ANLN in the Tg26 HIVAN model. Urine albumin and creatinine ratio at 8, 12, and 16 weeks were similar between double ANLNx Tg26 heterozygotes compared to Tg26 HIVAN mice (p=1.038, 0.0863. 0.0761 for each time-point). Mice heterozygous for both the ANLNx and Tg26 alleles also did not display any increase in survival compared to mice carrying only the Tg26 allele (p=0.361). Evaluation and scoring of PAS stained kidney sections by independent pathologists revealed similar levels of sclerosis between Tg26 HIVAN mice and mice heterozygous for both the ANLNx and Tg26 alleles.

Conclusion

Genetic ablation of ANLN does not improve kidney disease phenotypes in Tg26 HIVAN mice. ANLN upregulation likely represents a survival mechanism in Tg26 HIVAN mice and not a cause of injury.

Funding

  • NIDDK Support