Kidney Week

Abstract: SA-PO0277

TMEM16A/CLCA1 Activation Drives Tubular Dilation and Crystal Clearance in Calcium Oxalate Nephropathy

Session Information

• AKI: Mechanisms - Cell Signaling
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Holznecht, Nickolas J., University of California Santa Barbara, Santa Barbara, California, United States

Nickolas J. Holznecht, MS

• Strubl, Sebastian, University of California Santa Barbara, Santa Barbara, California, United States

Sebastian Strubl, MD

• Torres, Jacob A., University of California Santa Barbara, Santa Barbara, California, United States

Jacob A. Torres, PhD

• Shapiro, Maria, University of California Santa Barbara, Santa Barbara, California, United States

Maria Shapiro

• Cao, James Ting, University of California Santa Barbara, Santa Barbara, California, United States

James Ting Cao

• Arroyo, Alejandra, University of California Santa Barbara, Santa Barbara, California, United States

Alejandra Arroyo

• Tonum, Kanlayanee, Mahidol University Faculty of Science, Bangkok, Thailand

Kanlayanee Tonum, PhD, RPh

• Soodvilai, Sunhapas, Mahidol University Faculty of Science, Bangkok, Thailand

Sunhapas Soodvilai

• Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States

Thomas Weimbs, PhD

Background

Tubular retention of calcium oxalate (CaOx) crystals drives nephrolithiasis. We tested whether TMEM16A (Ca-activated Cl channel) and its regulator CLCA1 mediate tubular dilation to promote crystal clearance and examined STAT3/STAT6 as transcriptional regulators, primary cilia as determinants of recovery, and urinary CLCA1 as a tubular biomarker.

Methods

C57BL/6J male mice received 0.67% sodium oxalate (NaOx) chow for 3–14 days with DMSO vehicle, TMEM16A inhibitor (10 mg/kg SID i.p.), Ksp:cre STAT3 KO, STAT6 KO, or primary cilia disruption (Ift88 cKO). Endpoints: histopathology, immunofluorescence, Western blot, qRT-PCR, patch-clamp, 24-hour urine output, serum creatinine, and urinary CLCA1 ELISA.

Results

NaOx feeding induced rapid CaOx crystal deposition renal tubules, with TMEM16A/CLCA1 upregulation and apical redistribution, tubular dilation, and increased urine output. TMEM16A inhibition abolished tubular dilation and crystal clearance, increased crystal retention, and caused mortality. STAT3 KO impaired proximal TMEM16A/CLCA1 induction and dilation; STAT6 KO impaired distal dilation without mortality. Ift88 cKO mice showed failure to return to tubular diameter post-crystal clearance; survivors developed persistent dilation and cystogenesis. Urinary CLCA1 correlated with crystal burden and tubular dilation.

Conclusion

TMEM16A/CLCA1 function is essential for CaOx-induced water secretion, tubular dilation, crystal clearance and urine output; absence is lethal. STAT3 and STAT6 govern segment-specific responses. Primary cilia are required for morphological recovery and cyst prevention. Urinary CLCA1 is a candidate biomarker of tubular secretory activation.

Funding

• NIDDK Support