The spatiotemporal and paradoxical roles of NRF2 in renal toxicity and kidney diseases

Over 10% of the global population is at risk to kidney disorders. Nuclear factor erythroid-derived 2-related factor 2 (NRF2), a pivotal regulator of redox homeostasis, orchestrates antioxidant response that effectively counters oxidative stress and inflammatory response in a variety of acute pathophysiological conditions, including acute kidney injury (AKI) and early stage of renal toxicity. However, if persistently activated, NRF2-induced transcriptional cascade may disrupt normal cell signaling and contribute to numerous chronic pathogenic processes such as fibrosis. In this concise review, we assembled experimental evidence to reveal the cell- and pathophysiological condition-specific roles of NRF2 in renal chemical toxicity, AKI, and chronic kidney disease (CKD), all of which are closely associated with oxidative stress and inflammation. By incorporating pertinent research findings on NRF2 activators, we dissected the spatiotemporal roles of NRF2 in distinct nephrotoxic settings and kidney diseases. Herein, NRF2 exhibits diverse expression patterns and downstream gene profiles across distinct kidney regions and cell types, and during specific phases of nephropathic progression. These changes are directly or indirectly connected to altered antioxidant defense, damage repair, inflammatory response, regulated cell death and fibrogenesis, culminating ultimately in either protective or deleterious outcomes. The spatiotemporal and paradoxical characteristics of NRF2 in mitigating nephrotoxicity suggest that translational application of NRF2 activation strategy for prevention and interventions of kidney injury are unlikely to be straightforward - right timing and spatial precision must be taken into consideration.