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Abstract: TH-PO443

Blocking CHOP-Dependent TXNIP Shuttling to Mitochondria Attenuates Albuminuria and Mitigates Kidney Injury in Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Park, Sun-Ji, Washington University in St Louis, St Louis, Missouri, United States
  • Kim, Yeawon, Washington University in St Louis, St Louis, Missouri, United States
  • Li, Chuang, Washington University in St Louis, St Louis, Missouri, United States
  • Suh, Junwoo, Case Western Reserve University, Cleveland, Ohio, United States
  • Sivapackiam, Jothilingam, Washington University in St Louis, St Louis, Missouri, United States
  • Mangetti Gonçalves, Tássia, Washington University in St Louis, St Louis, Missouri, United States
  • Jarad, George, Washington University in St Louis, St Louis, Missouri, United States
  • Zhao, Guoyan, Washington University in St Louis, St Louis, Missouri, United States
  • Urano, Fumihiko, Washington University in St Louis, St Louis, Missouri, United States
  • Sharma, Vijay, Washington University in St Louis, St Louis, Missouri, United States
  • Chen, Ying Maggie, Washington University in St Louis, St Louis, Missouri, United States
Background

Albuminuria, a defining feature of glomerular disease, also leads to glomerulosclerosis and interstitial fibrosis. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly understood.

Methods

We utilized hereditary nephrotic syndrome (NS) (Lamb2-/- mice) and adriamycin-induced NS models, Chop-/- and Txnip-/- mice to investigate the regulation and function of TXNIP (thioredoxin-interacting protein). Glomeruli and tubule isolation, primary podocyte and tubular cell culturing, mitochondrial and nuclear fractionation, as well as confocal and electron microscopy were employed. Mitochondrial reactive oxygen species (ROS) levels were assessed by flow cytometry in cells and by 68Ga-Galuminox PET/CT imaging in live animals for the first time.

Results

we have identified CHOP (C/EBP homologous protein)-TXNIP as critical molecular linkers between albuminuria-induced endoplasmic reticulum (ER) dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1) and mitochondrial Trx2. However, little is known about the regulation and function of TXNIP in NS. TXNIP gene expression correlates with disease severity and decline of kidney function in human proteinuric kidney disease based on Nephroseq database. We demonstrate that CHOP upregulation induced by albuminuria drives TXNIP induction in both podocytes and tubules, as well as TXNIP shuttling from nucleus to mitochondria, where it is required for mitochondrial ROS production. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial NLRP3 to activate inflammasome, as well as releasing mitochondrial apoptosis signal-regulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1-dependent mitochondria apoptosis, thereby improving kidney function in NS.

Conclusion

NS is a leading cause of chronic kidney disease affecting 500 million people worldwide. Targeting TXNIP represents a promising therapeutic strategy for the treatment of NS.

Funding

  • NIDDK Support