Keap1-independent Nrf2 regulation: A novel therapeutic target for treating kidney disease

The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of antioxidant responses in mammals, where it plays a critical role in detoxification, maintaining cellular homeostasis, combating inflammation and fibrosis, and slowing disease progression. Kelch-like ECH-associated protein 1 (Keap1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, serves as a critical sensor of oxidative and electrophilic stress, regulating Nrf2 activity by sequestering it in the cytoplasm, leading to its proteasomal degradation and transcriptional repression. However, the clinical potential of targeting the Keap1-dependent Nrf2 regulatory pathway has been limited. This is evidenced by early postnatal lethality in Keap1 knockout mice, as well as significant adverse events after pharmacological blockade of Keap1 in human patients with Alport syndrome as well as in those with type 2 diabetes mellitus and chronic kidney disease. The exact underlying mechanisms remain elusive, but may involve non-specific and systemic activation of the Nrf2 antioxidant response in both injured and normal tissues. Beyond Keap1-dependent regulation, Nrf2 activity is modulated by Keap1-independent mechanisms, including transcriptional, epigenetic, and post-translational modifications. In particular, GSK3β has emerged as a critical convergence point for these diverse signaling pathways. Unlike Keap1-dependent regulation, GSK3β-mediated Keap1-independent Nrf2 regulation does not affect basal Nrf2 activity but modulates its response at a delayed/late phase of cellular stress. This allows fine-tuning of the inducibility, magnitude, and duration of the Nrf2 response specifically in stressed or injured tissues. As one of the most metabolically active organs, the kidney is a major source of production of reactive oxygen and nitrogen species and also a vulnerable organ to oxidative damage. Targeting the GSK3β-mediated Nrf2 regulatory pathway represents a promising new approach for the treatment of kidney disease.