Abstract
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis.
Highlights
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension
When Cys residues of Kelch-like ECH-associated protein 1 (KEAP1) protein are modified by sulfhydryl reactive chemicals, conformational KEAP1 changes lead to Nuclear factor erythroid-2 related factor 2 (NRF2) liberation and transcriptional activation of an array of antioxidant response element (ARE)-bearing genes, encoding detoxifying enzymes, reactive oxygen species (ROS) scavenging enzymes, thiol molecules, and their generating enzymes
In vitro experiments using the human renal tubular KH11 cell line showed that oxidative damages by mannitol or high glucose plus palmitate were attenuated by SFN incubation; protection was lost following NRF2 siRNA introduction
Summary
Oxidative stress is produced when reactive oxygen species (ROS) production goes over the limit of the capacity of the antioxidant defense systems of the body [10]. This is a common phenomenon found in CKD lesions, and is considered to play a critical role in both the progression of CKD and related complications [10,11,12]. 12/15-lipoxygenase was significantly up-regulated in the renal cortex of high-calorie/high-fat diet fed mice, which is a model of pre-diabetic neuropathy [25] Another source of ROS production comes from activation of renin-angiotensin system (RAS). Transgenic mice with CAT overexpression showed renoprotective effects following streptozotocin (STZ) treatment [30]
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