title: Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases.
abstract: Oxidative stress, including the generation of reactive oxygen species (ROS), appears to be responsible for the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), and for the progression of CKD to end-stage renal disease. The processes for oxidative stress include increased generation and decreased elimination of ROS that could be caused by an impaired antioxidant defense system. Nuclear factor-erythroid-2-related factor 2 (Nrf2) helps protect the kidney against oxidative stress by playing a pivotal role in the cooperative induction of genes that encode antioxidant and detoxifying enzymes. Nrf2 is confined to the cytoplasm as an inactive complex bound to a repressor Kelch-like ECH-associated protein 1 (Keap1), which facilitates ubiquitination of Nrf2. Studies using CKD model animals showed that despite stimulated oxidative stress the nuclear Nrf2 level was suppressed, which led to downregulation of the antioxidant enzymes. Hence, deterioration in Nrf2-Keap1 signaling could contribute to the severity of oxidative stress and the progression of CKD. By contrast, acute kidney injury (AKI) induces activation of renal Nrf2. Nrf2 activators or its proteasomal degradation inhibitors enhance nuclear Nrf2 translocation, inducing potential renoprotective actions against CKD and AKI. In both chronic and acute kidney diseases, sulfate-conjugated uremic toxins appear to enhance ROS production when accumulated in renal cells. An intestinal indole adsorbent ameliorates the progression of CKD by decreasing accumulation of indoxyl sulfate. Therapeutic approaches to prevent oxidative stress via activation of the Nrf2-Keap1 signaling and/or suppression of uremic toxin-induced ROS production could be effective strategies for maintaining kidney function.
authors: Department of Pharmacy, Kumamoto University Hospital, Honjo, Kumamoto 860-8556, Japan. saitohide@fc.kuh.kumamoto-u.ac.jp
authors: Hideyuki
authors: H
authors: Saito
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002908:Chronic Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C445068:bardoxolone methyl