Kidney Week

Abstract: TH-PO443

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

Session Information

• Glomerular Diseases: Podocytopathies and Nephrotic Syndromes
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Park, Sun-Ji, Washington University in St Louis, St Louis, Missouri, United States

Sun-Ji Park,

• Kim, Yeawon, Washington University in St Louis, St Louis, Missouri, United States

Yeawon Kim,

• Li, Chuang, Washington University in St Louis, St Louis, Missouri, United States

Chuang Li,

• Suh, Junwoo, Case Western Reserve University, Cleveland, Ohio, United States

Junwoo Suh,

• Sivapackiam, Jothilingam, Washington University in St Louis, St Louis, Missouri, United States

Jothilingam Sivapackiam,

• Mangetti Gonçalves, Tássia, Washington University in St Louis, St Louis, Missouri, United States

Tássia Mangetti Gonçalves,

• Jarad, George, Washington University in St Louis, St Louis, Missouri, United States

George Jarad,

• Zhao, Guoyan, Washington University in St Louis, St Louis, Missouri, United States

Guoyan Zhao,

• Urano, Fumihiko, Washington University in St Louis, St Louis, Missouri, United States

Fumihiko Urano,

• Sharma, Vijay, Washington University in St Louis, St Louis, Missouri, United States

Vijay Sharma,

• Chen, Ying Maggie, Washington University in St Louis, St Louis, Missouri, United States

Ying Maggie Chen,

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 – Mallinckrodt Pharmaceutical