Kidney Week

Abstract: FR-PO0702

Loss of SMPDL3b Induces Podocytopathy and Nephrotic Syndrome via Dysregulation of Cytidine Diphosphate (CDP)-Choline Metabolism and Store-Operated Calcium (Ca2+) Entry

Session Information

• Pediatric Nephrology: CKD, ESKD, and Glomerular Diseases
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Li, Guangbi, Virginia Commonwealth University, Richmond, Virginia, United States

Guangbi Li, PhD

• Zou, Yao, Virginia Commonwealth University, Richmond, Virginia, United States

Yao Zou

• Li, Ningjun, Virginia Commonwealth University, Richmond, Virginia, United States

Ningjun Li, MD

• Gehr, Todd W., Virginia Commonwealth University, Richmond, Virginia, United States

Todd W. Gehr, MD, FASN

• Li, Pin-lan, Virginia Commonwealth University, Richmond, Virginia, United States

Pin-lan Li, MD, PhD

• Kidd, Jason M., Virginia Commonwealth University, Richmond, Virginia, United States

Jason M. Kidd, MD, FASN

Background

Downregulation of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in podocytes is a hallmark of idiopathic nephrotic syndrome (NS) in children.

Methods

However, whether loss of SMPDL3b alone is sufficient to induce podocytopathy and NS remains unknown.

Results

In this study, we confirmed that SMPDL3b was abundantly expressed in podocytes of wild type (WT) mice but absent in podocytes of Smpdl3b knockout (KO) mice. KO mice exhibited no overt glomerular abnormalities under light microscope, but developed significant proteinuria and albuminuria. Transmission electron microscopy revealed classic minimal change disease-like features, including diffuse foot process effacement, microvillus formation, and vacuolation in podocytes. To investigate underlying mechanisms, we isolated primary podocytes from WT and KO mice. SMPDL3b has been traditionally regarded as a sphingolipid-metabolizing enzyme, but structural studies indicate it preferentially cleaves CDP-choline to generate choline, a putative intracellular messenger. LC-MS/MS analysis confirmed reduced CDP-choline and elevated choline in KO podocytes compared to WT podocytes. Immunofluorescent staining of F-actin and paxillin (focal adhesion marker) revealed that Smpdl3b gene deletion disrupted actin cytoskeleton and markedly reduced focal adhesion in podocytes, which was reversed by choline and phosphocholine, but not CDP-choline treatment. Atom force microscopy confirmed that reduced cellular elasticity in Smpdl3b KO podocytes was restored by choline and phosphocholine, but not CDP-choline. The therapeutic effects of phosphocholine were blocked by pre-treatment with Lansoprazole (a phosphocholine phosphatase inhibitor), implicating choline as the active product. Mechanistically, Smpdl3b deletion enhanced STIM1-Orai1 interaction and increased store-operated Ca²⁺ entry (SOCE), which were suppressed by choline and phosphocholine but not CDP-choline. Lansoprazole pre-treatment similarly blocked phosphocholine’s effects, further supporting the role of choline.

Conclusion

Taken together, our findings demonstrate that SMPDL3b is essential for maintaining podocyte structural and functional integrity. Loss of SMPDL3b may induce podocytopathy via disrupted CDP-choline metabolism, reduced choline signaling, and aberrant Ca²⁺ influx through Orai1 channels.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025z6y41g6e