Kidney Week

Abstract: TH-PO0287

SMPDL3b-Driven STING Signaling and Lipid Droplet Accumulation in Glomerular Diseases

Session Information

• Glomerular Diseases: Cell Biology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Saadat, Saeida, University of Miami Miller School of Medicine, Miami, Florida, United States

Saeida Saadat, PhD

• Fontanella, Antonio Miguel, University of Miami Miller School of Medicine, Miami, Florida, United States

Antonio Miguel Fontanella

• Njeim, Rachel, University of Miami Miller School of Medicine, Miami, Florida, United States

Rachel Njeim, PharmD, PhD

• Molina David, Judith T., University of Miami Miller School of Medicine, Miami, Florida, United States

Judith T. Molina David, PhD

• Mallela, Shamroop Kumar, University of Miami Miller School of Medicine, Miami, Florida, United States

Shamroop Kumar Mallela, PhD

• Merscher, Sandra, University of Miami Miller School of Medicine, Miami, Florida, United States

Sandra Merscher, PhD

• Fornoni, Alessia, University of Miami Miller School of Medicine, Miami, Florida, United States

Alessia Fornoni, MD, PhD, FASN

• Burke, George William, University of Miami Miller School of Medicine, Miami, Florida, United States

George William Burke, MD

• Mitrofanova, Alla, University of Miami Miller School of Medicine, Miami, Florida, United States

Alla Mitrofanova, PhD

Background

Glomerular diseases remain the leading cause of end-stage kidney failure worldwide. Our recent works and studies from others point to the disrupted sphingolipid metabolism, endoplasmic reticulum (ER) dysfunction, innate immune activation via stimulator of interferon genes (STING) and lipid droplet (LD) accumulation in podocytes as key contributors to glomerular diseases progression. Sphingolipid SMPDL3b (sphingomyelin phosphodiesterase acid-like 3b), a lipid-modifying enzyme enriched in lipid rafts and LD, is upregulated in glomerular diseases and drives podocyte injury. A major gap remains in understanding how sphingolipid remodeling alters ER membrane properties to activate innate immune pathways, including the STING pathway, and thereby promotes LD accumulation and podocyte injury.

Methods

We used human podocytes overexpressing SMPDL3b (SMP^OE) to examine LD accumulation, STING activation, ER morphology, and unfolded protein response (UPR) signaling. ER ultrastructure was assessed by transmission electron microscopy, transcriptomic changes were evaluated by bulk RNA-seq and UPR was assessed by Western blotting. In vivo studies were performed in mice with podocyte-specific Smpdl3b overexpression (pSMP^Tg). Pharmacologic STING activation (c-diAMP, 50mg/kg) was used in pSMP^Tg mice to evaluate effects on albuminuria, podocyte injury, and LD accumulation.

Results

SMPDL3b overexpression increases STING expression, promotes LD accumulation, and impairs ER morphology and stress response signaling in vitro and in vivo. We further show that genetic or pharmacologic STING inhibition reduces LD accumulation and kidney injury in mouse models of glomerular diseases with SMPDL3b overexpression.

Conclusion

These findings support a model in which SMPDL3b promotes ER membrane perturbation, leading to RSAD2-dependent STING activation and subsequent LD accumulation in podocytes. This newly identified SMPDL3b-RSAD2-STING-LD axis may represent a promising therapeutic target.

Funding

• Private Foundation Support