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Kidney Week

Abstract: FR-PO079

GSK3β-Mediated Keap1-Independent Regulation of Nrf2 Antioxidant Response: A Molecular Rheostat of AKI-to-CKD Transition

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Lu, Minglei, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
  • Liu, Zhangsuo, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States
Background

How acute kidney injury(AKI) is transformed to chronic kidney disease(CKD) remains elusive. Evidence suggests that glycogen synthase kinase(GSK)3β, a pivotal mediator of Keap1-independent regulation of Nrf2 defense, contributes to kidney injury. Whether GSK3β-mediated Nrf2 regulation is involved in AKI to CKD transition is unknown and was explored here.

Methods

Mice with renal tubule-specific GSK3β knockout and control mice were injured with folic acid. Nrf2 response and CKD transition were evaluated. In cultured renal tubular cells expressing GSK3β mutants, hydrogen peroxide-elicited chronic injuries and Nrf2 response were examined.

Results

Following folic acid injury, mice developed AKI with ensuing CKD transition, characterized by variable degrees of tubular cell atrophy, growth arrest and interstitial fibrosis. This lingering injury of renal tubules was parallelized by sustained oxidative stress that coincided with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes. The initiation of Nrf2 signaling, however, seems unaffected since cytoplasmic Nrf2 in injured tubules was persistently elevated. Moreover, renal expression of Keap1, a key repressor of Nrf2, was barely associated with the magnitude of CKD transition. In contrast, GSK3β was persistently overexpressed and hyperactive in renal tubules during CKD transition. Likewise, in patients who developed CKD following AKI related to diverse etiologies, GSK3β overexpression was evident in renal tubules and concomitant with impaired Nrf2 response and oxidative damages. Mechanistically, Nrf2 defense agaisnt oxidative stress was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3β in a Keap1-independent mode, in parallel with an exacerbated cell cycle arrest, dedifferentiation, apoptosis and extracellular matrix overproduction. Conversely, ectopic expression of dominant negative GSK3β reinforced Nrf2 response and diminished cytopathic changes. In vivo in folic acid-injured mice, targeting GSK3β in renal tubules via gene knockout or by microdose lithium reinstated Nrf2 response and hindered CKD transition.

Conclusion

GSK3β-regulated of Nrf2 may serve as a pragmatic therapeutic target for modifying the long-term sequelae of AKI.

Funding

  • NIDDK Support