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Abstract: TH-PO746

STING Activation by Mitochondrial DNA Triggers Podocyte Injury in Diabetic Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Fontanella, Antonio Miguel, University of Miami School of Medicine, Miami, Florida, United States
  • Njeim, Rachel, University of Miami School of Medicine, Miami, Florida, United States
  • Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
  • Burke, George William, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., 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 disease (DKD) remains the most common cause of end stage kidney disease in the USA, and is characterized by mitochondrial dysfunction, increased circulating serum mtDNA levels, and activation of STING, a DNA-sensing innate immune adaptor, expressed in podocytes. Mitochondrial DNA (mtDNA) has been previously described to activate STING signaling in renal tubular cells in DKD, leading to autoinflammation. We hypothesize that loss of mitochondrial transcription factor A (TFAM) and impairment of PTEN-induced putative kinase 1 (PINK1) mediated mitophagy triggers mtDNA leakage and causes podocyte injury in DKD.

Methods

16-week-old control (db/+) and diabetic (db/db) mice were used. Glomeruli were isolated to determine the expression of OXPHOS complex subunits, TFAM, PINK1 and TOM20, a biomarker for mitochondrial mass. Mitochondrial morphology was evaluated by TEM. Free mtDNA levels were measured in plasma, urine and cytosolic fractions from kidney cortex. Treatment with nuclear DNA (nDNA) or mtDNA was performed in vitro(10 ng, 30 min) using immortalized control human podocytes and in vivo (5 mg/kg, 24h) using control and STING knockout mice, followed by pSTING/STING expression and phenotypical analyses.

Results

We found that db/db mice have decreased glomerular TFAM expression and increased PINK1 expression in the mitochondrial fraction of db/db mice kidney cortices. Mitochondria morphology was indicative of dysfunction on TEM analysis, which was confirmed by increased expression of OXPHOS complex II (SDHA), and loss of mitochondrial mass marker TOM20. Db/db mice were also found to have increased mtDNA in the cytosol of kidney cortices, as well as in blood and urine. Treatment with mtDNA led to increases in pSTING expression in vitro and the development of albuminuria and foot process effacement in vivo, while STING -/- mice were protected from renal injury.

Conclusion

Our data suggest that loss of TFAM accumulation of PINK1 contribute to pathologic leakage of mtDNA into the circulation and cytosol causing albuminuria and podocyte injury.

Funding

  • NIDDK Support