ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO1012

A Novel Mutation in Podocyte-Specific Protease HtrA1 Is Associated with Glomerular Disease Progression

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
  • Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
  • Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

In kidney allografts, IGF-1 signaling was associated with reduced expression of Integrin A3, a key podocyte adhesion protein, and accelerated podocyte detachment. Insulin-like growth factor binding protein 2 (IGFBP2) and the high-temperature requirement factor A1 (HTRA1) contributed to the observed IGF-1 signaling. Podocyte specificity of HTRA1 was affirmed by single-cell RNA sequencing of healthy kidney tissue. The HTRA1 encodes a protease and makes bound IGF-1 locally bioavailable(doi.org/10.1016/s0014-5793(96)01229-x). Since 99% IGF-1 is bound, functional mutations in the HTRA1 gene could therefore perturb local IGF-1 signaling with functional consequences.

Methods

We searched for HTRA1 coding variants in the NEPTUNE cohort (n=620). Six distinct variants passed QC filtering. Each variant was then examined for its association with negative outcome (ESRD or 40% reduction in GFR). Transcriptional consequences on IGF-1 signaling of these mutations were evaluated in glomerular RNA-sequencing data.

Results

One variant was associated with a 2.7-fold increased risk of negative outcome. This relatively rare SNP (rs369149111); allele frequency-0.0248 results in a missense mutation, leading to alanine to valine change within the conserved signaling peptide (Ala20Val) region. Corresponding higher expression of IGF-1R in glomeruli as observed in patients with this variant.

Conclusion

SNP (rs369149111) is associated with glomerular disease progression. This rare allele likely interacts with glomerular IGF-1 signaling that then contributes to podocyte loss observed in glomerular diseases and transplanted kidneys. Further studies are necessary to confirm the prevalence and mechanistic implications of this HTRA1 variant

Funding

  • NIDDK Support