Anti-KEAP1 monoclonal antibody, clone 2G21C7

Kidney disease affects ~ 10% of the population worldwide, resulting in millions of deaths each year. Mechanistically, oxidative stress is a major driver of various kidney diseases, and promotes the progression from acute to chronic injury, as well as renal cancer development. NRF2, the master regulator of redox balance, has been shown to protect against kidney disease through its negation of reactive oxygen species (ROS). However, many kidney diseases exhibit high levels of ROS as a result of decreased NRF2 protein levels and transcriptional activity. Many studies have tested the strategy of using NRF2 inducing compounds to alleviate ROS to prevent or slow down the progression of kidney diseases. Oppositely, in specific subsets of renal cancer, NRF2 is constitutively activated and contributes to tumor burden and overall poor prognosis; therefore, there has been a recent interest in studies investigating the benefits of NRF2 inhibition. In this review, we summarize recent literature investigating the role of NRF2 and oxidative stress in various kidney diseases, and how pharmacological modification of NRF2 signaling could play a protective role.

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a levels and increased the expression of kelch- like ECH-associated protein 1 (Keap1) - a target of miR-200a and a negative regulator of NRF2. This led to the inactivation of NRF2 signaling and exacerbation of OS and inflammation. miR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG conditions. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a's actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity, which protects against diabetic ED.