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Abstract: PO2502

Wasp Homologue Associated with Membranes and Microtubules Is a Kidney Disease Risk Gene

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Mukhi, Dhanunjay, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Doke, Tomohito, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Group or Team Name

  • Institutes of Diabetes Obesity & Metabolism
Background

Genome-wide association studies identified hundreds of risk variants that are associated with kidney function traits. More than 90% of these variants are located in non-coding region of the genome and therefore their target genes, target cell type and encoded molecular pathways remain not known.

Methods

Here we used human kidney expression and methylation of quantitative trait (eQTL and mQTL) information and complex computational integration to identify target cell types for genetic variants. We obtained mice with genetic loss of WHAMM. We induced acute kidney injury by cisplatin injection and chronic disease by folic acid injection. Kidney function was analyzed by serum creatinine and blood urea nitrogen, real time PCR, western blotting, and histology analyses. We cultured primary kidney tubule epithelial cells, in addition, autophagy was assessed by ptf-LC3B GFP-RFP plasmid and mitophagy was assessed by using mitoCox- VIII GFP-RFP plasmid.

Results

Using Bayesian colocalization, summary mendelian randomization, and transcriptome-wide association studies we prioritized WHAMM as a kidney disease risk gene. Risk variant rs12903411 was associated with higher WHAMM expression. WHAMM is an Arp2/3 complex activator protein that is associated with membrane dynamics by utilizing microtubules. WHAMM heterozygous and knock-out mice subjected to cisplatin and folic acid injury presented with improved kidney function (BUN, creatinine) and lower expression of injury markers (Kim1, N-gal) and fibrosis markers. Primary tubular cells with WHAMM loss showed increased autophagy flux compared to wild type. Furthermore, WHAMM heterozygous and knock-out mice and cells showed improved mitophagy and reduced expression of inflammatory markers such as IL-1β, IL-18 and Nlrp3. Mice with genetic deletion of WHAMM showed lower pyroptosis indicated by cleaved caspase1 and gasdermin D levels compared to WT mice in the folic acid model.

Conclusion

In summary, this study identified WHAMM as a new kidney disease risk gene.

Funding

  • NIDDK Support