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

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.

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“…Under basal conditions, KEAP1 binds and sequesters NRF2 in cytoplasm for proteasome degradation, whereas NRF2 can evade the repression of KEAP1 and translocate into nucleus to initiate the transcription of target genes 11 . Apart from KEAP1, NRF2 can be regulated by other factors 12,13 , such as WDR23-DDB1-CUL4 regulatory axis 14 and miRNAs related mechanisms 15,16 . Recent study has shown that NRF2 is the main target of radiosensitive agent salinomycin in NPC cells 17 , however, the expression pattern of NRF2, and its activation mechanism in NPC remains unknown.…”

Protective Role of Nrf2 in Renal Disease

“…In cisplatin-AKI, DMF also reduced peritubular fibrosis [ 184 ]. In a mouse model of folic acid-induced AKI, specific deletion of GSK3β in renal tubules or treatment with a GSK3β inhibitor improved the Nrf2 antioxidant response, independently of Keap1, protecting from AKI to CKD transition [ 185 ].…”

Purified Sika deer antler protein attenuates GM-induced nephrotoxicity by activating Nrf2 pathway and inhibiting NF-κB pathway

“…Because of persistent oxidative stress, the cell programs its death by apoptosis to prevent degeneration and proliferation in an uncontrollable way 14 . Activation of Nrf2 can alleviate the toxicity related to reactive oxygen species and is an important molecular target for the prevention of renal injury 15 .…”