Kidney Week

Abstract: FR-OR033

Genomic and Molecular Evidence Implicates ZFP36 as Coregulator of Volume Balance and Inflammation

Session Information

• Electrolyte and Acid-Base Homeostasis: New Insights
  October 23, 2026 | Location: Room 405, Convention Center
  Abstract Time: 05:20 PM - 05:30 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Arace, Jeffrey, Columbia University, New York, New York, United States

Jeffrey Arace, MD

• Khan, Atlas, Columbia University, New York, New York, United States

Atlas Khan, MS, PhD, FASN

• Shen, Tian, Columbia University, New York, New York, United States

Tian Shen, PhD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

• Barasch, Jonathan M., Columbia University, New York, New York, United States

Jonathan M. Barasch, MD, PhD

Background

There is growing evidence that inflammatory cytokines promote fluid retention and salt-sensitive hypertension. We investigated the role of ZFP36. a mRNA-binding protein that destabilizes cytokine transcripts, as potential a potential co-regulator of genitourinary (GU) tract inflammation and fluid balance.

Methods

We performed a rare variant gene-based collapsing meta–phenome-wide association study (meta-PheWAS) across the UK Biobank (N=469,835) and All of Us (N=245,388) cohorts to identify phenotypic associations with rare (MAF<0.001), likely deleterious (CADD>20) human ZFP36 missense variants. To investigate the role of ZFP36 in fluid balance and inflammation; we subjected wild-type and Zfp36 KO mice to volume depletion and urinary tract infection (UTI). We then measured urinary biomarkers of tubular injury (Ngal & Kim-1) and performed immunohistochemistry, in situ hybridization, and RNA sequencing in the bladder and kidney.

Results

In our meta-PheWAS, we detected an association of rare, likely deleterious human missense variants in ZFP36 with "Fluid Overload" (OR=3.6, P=1.6E-05) and "Chronic Interstitial Cystitis" (OR=12.6, P=1.6E-05) (Bonferroni threshold=0.05/1,817 Phecodes =2.7E-05). Zfp36 expression was markedly increased in the GU tract of mice following either volume depletion or UTI, consistent with a role in maintaining fluid and immune homeostasis. Urinary Ngal and Kim-1 levels were increased by volume depletion in Zfp36 KO mice but not in controls. UTI in Zfp36 KO mice induced kidney and bladder expression of inflammatory cytokines, including TNF-α, IL-1β, and others that have been implicated in renal sodium handling. Excessive neutrophil extravasation was observed in Zfp36 KO in UTI. In wild-type mice, infected superficial urothelial cells of the bladder are shed as a protective response; however, Zfp36 KO mice demonstrated dysregulated shedding. This phenotype was accompanied by increased Gsdmd expression, linking loss of Zfp36 to altered pyroptotic signaling and defective epithelial cell turnover.

Conclusion

We identify the mRNA binding protein ZFP36 as a potential co-regulator of fluid balance and the immune response and describe a novel molecular and genetic link between renal sodium handling and inflammation.

Funding

• Other NIH Support