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Abstract: PO0651

Activation of STING Causes Proteinuria in Mice and Contributes to Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Fontanella, Antonio Miguel, University of Miami School of Medicine, Miami, Florida, United States
  • Tolerico, Matthew, University of Miami School of Medicine, Miami, Florida, United States
  • Mallela, Shamroop Kumar, University of Miami School of Medicine, Miami, Florida, United States
  • Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
  • Kim, Jin Ju, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
  • Burke, George William, University of Miami School of Medicine, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
  • Mitrofanova, Alla, University of Miami School of Medicine, Miami, Florida, United States

Group or Team Name

  • Katz Family Division of Nephrology and Hypertension
Background

Diabetic kidney diseases (DKD) is one of the major health problems worldwide with no current cure. Podocytes express elements of the innate immune system which may contribute to chronic inflammation and glomerular damage. Stimulator of interferon genes (STING) was identified as a crucial regulator of the DNA sensing pathway and the cGAS-STING signaling pathway has been shown to regulate inflammation and energy homeostasis under obesity conditions, kidney fibrosis and acute kidney injury. Whether STING activation contributes to development and progression of DKD remains unknown. We tested the hypothesis that activation of STING causes podocyte damage and proteinuria in DKD.

Methods

c-diAMP treatment to inhibit STING (10μM) in immortalized human podocytes was performed for 24h. 8-week-old C57BL6 mice were IP-injected with a single dose of c-diAMP (25mg/kg) and sacrificed 72h after injection. 16-week-old db/db mice were used ito evaluate activation of STING in experimental DKD. 10-week-old db/db mice were IP-injected with C-176 (750nM), STING-specific antagonist, for 4 weeks daily. STZ injected STING knockout (STING-/-) and C57BL6 mice were also utilized. Blood and kidneys were harvested and processed for in-depth phenotypical analysis, including urinary albumin-to-creatinine ratio, histological analysis, transmission electron microscopy, glomeruli isolation and serum analysis.

Results

Podocytes showed expression all of the cGAS-STING components at mRNA and protein levels under physiological conditions and treatment with c-diAMP lead to activation of the cGAS-STING pathway. Treatment of C57BL6 mice with c-diAMP resulted in an increased expression of STING in kidney cortex and this was associated with increased urine ACR. STING activation is also implicated in glomerular injury in db/db mice at the baseline, which could be ameliorated with pharmacological (C-176) inhibition. In STZ model of DKD, STING-/- mice did not develop albuminuria and had no changes in their BUN, serum creatinine levels or histological abnormalities compared to STZ controls.

Conclusion

Our findings demonstrate an important role of the cGAS-STING signaling pathway in mediating the glomerular injury in DKD and provide an evidence for STING as a potential treatment target in DKD.

Funding

  • Private Foundation Support