Kidney Week

Abstract: TH-PO1131

The Actin and Microtubule Network Regulator WHAMM Is Identified as a Key Kidney Disease Risk Gene

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Mukhi, Dhanunjay, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Dhanunjay Mukhi, PhD

• Prasanna, Kolligundla Lakshmi, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Kolligundla Lakshmi Prasanna, PhD

• Doke, Tomohito, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Tomohito Doke, MD, PhD

• Silva, Magaiver Andrade, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Magaiver Andrade Silva, PhD

• Liu, Hongbo, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Hongbo Liu, PhD

• Palmer, Matthew, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Matthew Palmer, MD, PhD

• Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Katalin Susztak, MD, PhD

Group or Team Name

• Susztak Group.

Background

Nearly 850 million people suffer from kidney disease across the globe, yet the molecular mechanisms remain elusive. Recent genome-wide association studies identified genetic variants at more than 800 loci responsible for kidney dysfunction, however, target genes, target cell types, and underlying pathways remain poorly understood.

Methods

We utilized a comprehensive gene prioritization strategy involving multiple genetic evidence (kidney expression and methylation quantitative trait (eQTL & meQTL), allele-specific expression, snATAC-seq, Bayesian colocalization, and SMR, etc.) to identify the Wasp homolog associated with actin, membranes, and microtubules (WHAMM) as a causal gene for kidney dysfunction on chromosome 15. We obtained WHAMM genetic knockout mice and analyzed at baseline and after induction of acute kidney injury, chronic kidney disease by folic acid injection, and unilateral ureter obstruction (UUO). Serum creatinine, BUN, and cystatin C levels were measured. Gene expression and protein levels were measured by real-time PCR, western blotting, and immunofluorescence. Primary kidney tubule epithelial cells were analyzed for cytoskeleton changes, ASC-speckle formation, and cell death by confocal microscopy imaging. Autophagy was assessed by LC3 turnover at baseline and after induction of starvation, and cisplatin. We employed cytoskeletal inhibitors in both in vitro and in vivo studies to demonstrate the role of WHAMM in kidney disease.

Results

Here we show that nucleotide variants on chromosome 15 are not only associated with kidney dysfunction but also regulate the expression of WHAMM. WHAMM expression is higher in mice and patients with chronic and acute kidney disease. Genetic knockout of Whamm appeared healthy at baseline but showed less injury following cisplatin, folic acid, and unilateral ureteral obstruction. In vitro cell studies indicated that WHAMM controls cell death by regulating actin-mediated cytochrome c release from mitochondria and the formation of ASC-speckles. Pharmacological inhibition of actin dynamics was able to mitigate kidney disease development in experimental models.

Conclusion

Our study identifies a key role of WHAMM in the kidney disease development and the pharmacological modulation of this pathway as a potential therapeutic approach.

Funding

• NIDDK Support