GSK3β-mediated Keap1-independent regulation of Nrf2 antioxidant response: A molecular rheostat of acute kidney injury to chronic kidney disease transition

Minglei Lu,Pei Wang,Yingjin Qiao,Chunming Jiang,Yan Ge,Bryce Flickinger,Deepak K Malhotra,Lance D Dworkin,Zhangsuo Liu,Rujun Gong

doi:10.1016/j.redox.2019.101275

Abstract

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3β, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3β overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3β, but reinforced by ectopic expression of dominant negative GSK3β in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3β in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3β-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.

Highlights

Acute kidney injury (AKI) has been traditionally regarded as a selflimiting mild disease that reverses rapidly and spontaneously
To study the pathogenesis of AKI to chronic kidney disease (CKD) transition, we employed the murine model of folic acid nephropathy, which recapitulates a disease course featured by AKI during the initial acute phase that lasts for 3–5 days ensued by variable renal recovery and progression to CKD
To ascertain if impaired Nrf2 response is present in human AKI to CKD transition and associated with GSK3β hyperactivity as well, we examined kidney biopsy specimens from patients with progressive CKD that was developed after a documented antecedent episode of AKI due to diverse etiologies, including administration of iodinated radiocontrast media, contraction of the extracellular fluid volume and ingestion of aristolochic acid-containing herbs

Summary

Introduction

Acute kidney injury (AKI) has been traditionally regarded as a selflimiting mild disease that reverses rapidly and spontaneously. A growing body of evidence recently demonstrates that the number of patients with incomplete renal recovery might have been underestimated [3,4,5,6]. The pathogenic mechanisms by which AKI transforms into CKD remains to be defined, but there is evidence suggesting that. A number of pathogenic pathways have been implicated in incomplete recovery of tubular epithelial cells from AKI, including aberrant cell cycle arrest, hypoxia, lingering inflammation and others [10,13,14,15,16,17,18]. Regardless of the various etiologies of AKI, like acute ischemia reperfusion injuries, nephrotoxicity or urethral obstruction, all these pathways are both causes and consequences of excessive oxidative stress due to overproduction of reactive oxygen and nitrogen species (RONS). As a common denominator of both AKI and CKD, oxidative stress has been demonstrated to be responsible for failed tubular recovery after AKI and transition of AKI to CKD [11,19,20]

Methods

Results

Conclusion