Kidney Week

Abstract: SA-PO625

Mitochondrial Damage in Tubule Cells Activates the cGAS-STING Innate Immune Pathway and Leads to Fibrosis

Session Information

• Glomerular Diseases: Immunology, Inflammation - II
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Dhillon, Poonam, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Poonam Dhillon,

• Chung, Kiwung, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Kiwung Chung,

• Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Shizheng Huang,

• Sheng, Xin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Xin Sheng,

• Shrestha, Rojesh, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Rojesh Shrestha,

• Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Chengxiang Qiu,

• Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Jihwan Park,

• Palmer, Matthew, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew Palmer,

• Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak,

Group or Team Name

• Susztak's Lab

Background

Mitochondrial damage, defective bioenergetics, and immune system activation play key role in chronic kidney disease (CKD) and fibrosis. As the mitochondria retained ancient circular bacterial DNA, we hypothesized that the mitochondrial defects observed in kidney fibrosis lead to cytoplasmic leakage of the mitochondrial DNA and then recognized by the intracellular bacterial DNA recognition pathway; cGAS-STING signaling cascade resulting in activation of inflammatory pathways and CKD.

Methods

Here, we analyzed gene expression data by RNA sequencing of 433 microdissected human kidney tissue samples with varying degree of kidney fibrosis and kidney function. To model mitochondrial damage, we generated mice with tubule-specific mitochondrial transcription factor (Tfam) deletion (Ksp-Cre/Tfam^f/f). To explore the role of STING we crossed these mice with STING knock-out mice and treated with STING inhibitor. To understand the therapeutic potential of STING inhibition in CKD, we examined the renal phenotype of the STING knock-out mice following folic acid (FA) induced kidney injury and treated mice with a STING inhibitor.

Results

We found that expression of mitochondrial genes and its transcriptional regulator TFAM was significantly decreased in patients and mouse models with kidney disease. Ksp-Cre/Tfam ^f/f developed severe mitochondrial loss and decline of ATP content by 6 weeks of age. Progressive azotemia, kidney fibrosis and death of the animals was only observed after 12 weeks of age. Mechanistic studies demonstrated that aberrant mtDNA packaging upon TFAM deficiency in tubule cells resulted in escape of mtDNA into the cytosol, activation of the cytosolic DNA sensing pathway, STING, resulting in cytokine expression and immune cell recruitment. Genetic deletion or pharmacological inhibition of STING ameliorated TFAM-loss induced kidney fibrosis. Genetic deletion of STING and to lesser degree the STING inhibitor ameliorated kidney fibrosis in the FA induced model of kidney disease.

Conclusion

We concluded that in addition to its essential role in metabolism, TFAM sequesters mtDNA to prevent the activation of innate immune pathways and fibrosis. Cytosolic aberrant DNA in CKD activates the cGAS-STING pathway. Limiting STING activity can ameliorates kidney disease development.

Funding

• NIDDK Support