Kidney Week

Abstract: TH-OR013

Loss of Transcription Factor A (Mitochondrial, Tfam) in Tubule Cells Causes Renal Failure by Linking Metabolic Insufficiency to Enhanced Inflammation

Session Information

• CKD: Mechanisms of Kidney Fibrosis
  October 25, 2018 | Location: 9, San Diego Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

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

Kiwung Chung

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

Shizheng Huang,

• 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,

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

Katalin Susztak,

Background

Renal tubule cells have one of the highest mitochondrial density to keep up with their high energy need. Loss and dysfunction of mitochondria has been proposed to play key role in kidney disease development. On the other hand, the key transcriptional regulator that maintains mitochondrial integrity in renal tubule cells of healthy kidneys have not been defined.

Methods

To investigate the role of Tfam on renal tubule epithelial cells (TECs), we generated and characterized tubule specific Tfam (Transcription Factor A, mitochondrial) knock-out mice (Ksp cre/Tfam ^flox/flox). To perform in vitro mechanism studies, we cultured primary TECs from wild-type and WT/Tfam ^flox/flox mice and infected them with Ad5CMVCre adenovirus to delete Tfam.

Results

Tfam deficient mice were viable at birth but they died by 12 weeks of age. Blood chemistry indicated significant renal damage and azotemia. Structurally, the kidneys were enlarged, the tubules were dilated. There was an increase in inflammatory cells and matrix accumulation. Renal epithelial cells showed abnormally enlarged mitochondria and structural defect. Mitochondrial oxidative phosphorylation associated proteins were decreased with mild lipid accumulation. Mechanistic studies, using primary cultured tubule epithelial cells demonstrated that aberrant mtDNA packaging upon Tfam deficiency results in an escape of mtDNA into the cytosol. These events induced the activation of cytosolic DNA sensing pathway such as Stimulator of interferon genes (STING)-Cyclic GMP-AMP synthase (cGAS), and downstream NF-κB activation. The NF-κB activation was also evident in kidneys of the knock-out mice. Blunting of the NF-κB activation, reduced inflammatory gene expression, proliferation of tubule cells and protected from cellular dedifferentiation.

Conclusion

Collectively, we show Tfam maintains mitochondrial integrity and cellular metabolism at baseline. Loss of Tfam results in NF-κB activation linking metabolic signals to inflammation.

Funding

• NIDDK Support