Traditional Chinese Medicine Ameliorates Acute Kidney Injury and Chronic Kidney Disease by Enhancing Keap1/Nrf2 Pathway

INTRODUCTION Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are a global public health issue that ultimately results in end-stage renal disease.[1] Accumulating evidence suggests that oxidative stress and inflammation play pivotal roles in kidney disease.[1-3] The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a critical regulatory mechanism that enables an organism to counteract oxidative stress and inflammation, and it also retards kidney diseases.[2,3] Natural products, such as curcumin and sulforaphane, enhance the Keap1/Nrf2 pathway, which subsequently ameliorates kidney disease.[4] We therefore emphasized specific molecular mechanisms of the Keap1/Nrf2 pathway in regulating oxidative stress and inflammation in AKI and CKD and now explore the therapeutic potential of targeting this pathway for the improvement of kidney diseases. KEAP1/NRF2 PATHWAY AND OXIDATIVE STRESS AND INFLAMMATION IN KIDNEY DISEASE Inflammation can exacerbate oxidative stress by generating ROS and inducing apoptosis and necrosis, thereby further amplifying injury.[5] Nrf2 is a key regulator of cellular redox homeostasis and inflammatory responses.[6] This pathway maintains cellular redox balance by increasing the levels of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), while concurrently reducing intracellular reactive oxygen species (ROS) levels [Figure 1].[5-8]Figure 1.: Crosstalk between Keap1/Nrf2 pathway and IκB/NF-κB and TGF-β/Smad pathway. Upon ROS-induced disassociation with Keap1, the Nrf2 protein translocates into the nucleus, where it activates transcription of antioxidant genes. Nrf2 mitigates fibrosis by regulating the IκB/NF-κB and TGF-β/Smad pathways. Meanwhile, the natural product curcumin activates the Keap1/Nrf2 pathway by disrupting the Nrf2-Keap1 complex structure. 4-HNE, 4-hydroxynonenal; ARE, antioxidant response element; Iκκ, inhibitor of kappa B kinase; IκB, inhibitor of kappa B; IL-6, interleukin 6; MDA, malondialdehyde; Nrf2, nuclear factor erythroid 2-related factor 2; NF-κB, nuclear factor kappa B; P, phosphorus; P50, nuclear factor kappa B1; P65, RelA; ROS, reactive oxygen species; sMaf, small Maf protein; TNF-α, tumor necrosis factor-α; TRAFs, tumor necrosis factor receptor-associated factors; Ub, ubiquitin; TGF-β/Smad, transforming growth factor-β/suppressor of mothers against decapentaplegic.Keap1/Nrf2 pathway and oxidative stress and inflammation in AKI A large body of evidence indicates that oxidative stress and inflammation are key pathogenic factors in AKI.[7,9,10] These two processes act synergistically to induce kidney damage and exacerbate disease severity.[10] In AKI, the mitochondrial electron transport chain is disrupted, leading to excessive consumption of adenosine triphosphate.[7,10] In addition, oxygen resupply during reperfusion increases electron leakage and ROS generation.[7,10] Such a massive accumulation of ROS damages renal cells, particularly renal tubular epithelial cells, by oxidizing various biological macromolecules.[7,10] Moreover, ROS attack intracellular unsaturated fatty acids, generating lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal, which destroys cell structure and induces apoptosis [Figure 2].[7,9,10] Additionally, ROS is a key mediator of inflammation,[6] activating pro-inflammatory pathways, such as the inhibitor of kappa B (IκB)/nuclear factor kappa B (NF-κB) pathway, which induces the expression of pro-inflammatory cytokines and amplifies inflammatory reactions.[1,5,10] This aggravates renal tubular injury through the recruitment of immune cells and further release of ROS [Figure 1].[1,5,10]Figure 2.: Keap1/Nrf2 pathway regulates intracellular metabolic disorders. Accumulating ROS exacerbate inflammation by inducing abnormal glucose and lipid metabolism. However, natural products curcumin and sulforaphane activate the Keap1/Nrf2 pathway, thereby restoring mitochondrial function and alleviating inflammation. 4-HNE, 4-hydroxynonenal; ACC, acetyl-CoA carboxylase; AGEs, advanced glycation end products; CPT1, carnitine acyl transferase I; FAS, fatty acid synthase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSH, oxidized glutathione; HK, hexokinase; IL-6, interleukin 6; MDA, malondialdehyde; NF-κB, nuclear factor kappa B;PDH, pyruvate dehydrogenase; PK, pyruvate kinase; ROS, reactive oxygen species; succinyl-CoA, succinyl coenzyme A; TLR9, toll-like receptor 9; TNF-α, tumor necrosis factor-α; α-KG, α-ketoglutaric acid.During reperfusion, the accumulation of ROS triggers dissociation of the Keap1/Nrf2 complex, activates the Keap1/Nrf2 pathway, and initiates the transcription of downstream antioxidant genes to counteract oxidative stress-induced kidney damage.[1,7,9] During this process, HO-1 can inhibit the phosphorylation of NF-κB, downregulate inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and reduce infiltration of inflammatory cells.[6,7] By activating a repertoire of antioxidant enzymes, the Keap1/Nrf2 pathway effectively reduces intracellular ROS levels, thereby alleviating AKI that is induced by oxidative stress and inflammatory responses [Figure 1].[7] In one study, Nrf2-deficient mice exhibited an exacerbated inflammatory response and intensified lipid peroxidation in AKI, which confirms that Nrf2 is a key target for alleviating the development and progression of AKI.[6] Keap1/Nrf2 pathway and oxidative stress and inflammation in CKD Studies have demonstrated that metabolic disorders, such as abnormal glucose and lipid metabolism and mitochondrial dysfunction mediated by the dysregulation of the Keap1/Nrf2 pathway, are closely associated with the progression of CKD.[1,6] However, activation of the Keap1/Nrf2 pathway can effectively inhibit renal fibrosis.[6] Nrf2 not only directly regulates the expression of pro-fibrotic proteins by inhibiting the transforming growth factor-β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) pathway, it can also upregulate Smad7 content to promote competition with Smad3, thereby jointly regulating renal fibrosis [Figure 1].[6] In diabetic kidney disease (DKD), dysregulation of blood glucose and lipids metabolism can exacerbate oxidative damage and inflammatory responses in the kidneys.[6] Persistently elevated blood glucose levels promote the formation of advanced glycation end products (AGEs),[4] and high levels of AGEs activate the NF-κB pathway, inducing the accumulation of ROS and inflammatory responses [Figure 2].[4] Elevated ROS levels induce abnormal mitochondrial metabolism and exacerbate mitochondrial damage, thereby accelerating the progression of DKD.[4] Hyperglycemia and oxidative stress also stimulate the production of chemokines, which further induce inflammatory responses in DKD.[4] Additionally, macrophages recruited during the inflammatory process generate large quantities of ROS, which exacerbates oxidative damage.[4] In turn, high levels of ROS activate the Keap1/Nrf2 pathway, prompting antioxidant enzymes to scavenge ROS and alleviate oxidative stress.[4] Nrf2 can regulate glucose and lipid metabolism, improve mitochondrial dysfunction, and enhance insulin sensitivity.[4,6] In a study, the expression of pro-inflammatory factors and fibrotic markers increased in Nrf2-deficient CKD mice,[6] indicating that Nrf2 is an effective therapeutic target for treating CKD. NATURAL PRODUCTS ATTENUATE KIDNEY DISEASE BY TARGETING KEAP1/NRF2 PATHWAY In AKI, magnolol and Lycium barbarum polysaccharides alleviate inflammation by activating the Keap1/Nrf2 pathway.[7,9] Astragalus polysaccharides, hesperidin, and luteolin activate Nrf2 and increase HO-1 and SOD activities, thereby alleviating AKI by reducing ROS accumulation.[9] Furthermore, astragaloside IV alleviates AKI by regulating the Nrf2 pathway and inhibiting free fatty acid-induced cell apoptosis.[9] In addition to activating the Nrf2 pathway, betulinic acid, berberine, and hesperetin inhibit the NF-κB pathway and improve AKI by modulating oxidative stress, inflammation, and mitochondrial dysfunction.[9] In renal fibrosis, oleanolic acid promotes nuclear translocation of Nrf2, reduces lipid peroxidation reactions, and restores intracellular oxidative balance, thereby alleviating disease progression.[7] Also, sinomenine activates Nrf2, which regulates the expression of downstream genes and modulates an organism’s oxidative stress response.[7] Activation of Nrf2 also regulates the TGF-β pathway, thereby exerting an antifibrotic effect.[6,7] Additionally, epigallocatechin-3-gallate modulates Nrf2 and NF-κB nuclear translocation and inhibits the TGF-β pathway.[6,10] By enhancing the activity of antioxidant enzymes, it protects kidneys against inflammation and oxidative damage, thereby effectively alleviating renal interstitial fibrosis.[6,10] In DKD, sulforaphane and resveratrol activate Nrf2 and promote expression of its downstream genes, upregulating antioxidant enzymes and reducing intracellular ROS levels to protect renal cells.[6,8] They also regulate the NF-κB pathway to reduce inflammation.[4,6] Similarly, curcumin activates the Nrf2 pathway by disrupting the Nrf2-Keap1 complex, which increases the number of antioxidant enzymes, reducing inflammation and oxidative damage [Figure 1].[4,10] CONCLUSION AND PERSPECTIVE In AKI and CKD, hyperactivated inflammation and oxidative stress are core factors driving kidney damage. The Keap1/Nrf2 pathway is crucial for regulating cellular antioxidant and anti-inflammatory processes. Activating the pathway’s signaling inhibits an oxidative stress cascade, reduces inflammatory cell infiltration, and improves metabolic disorders, thereby delaying disease progression. This review emphasizes the specific role of the Keap1/Nrf2 pathway in alleviating oxidative stress and inflammatory response in acute and chronic kidney disease. Although existing studies have demonstrated the unique potential of natural products for targeting and activating the Keap1/Nrf2 pathway with the goal of improving acute and chronic kidney diseases, several challenges remain. Research on targeting the Keap1/Nrf2 pathway in kidney disease is still in the preclinical stage and faces challenges with being translated into clinical application. Additionally, activating the Keap1/Nrf2 pathway must be precisely tailored to the stage of disease progression. Given that kidney diseases are long-term, dynamic processes, current technologies face obstacles to achieving precise regulation of the Keap1/Nrf2 pathway. In conclusion, in-depth research into the molecular mechanisms by which natural products target and regulate the Keap1/Nrf2 pathway is highly valuable for the development of new therapeutic strategies to treat acute and chronic kidney diseases. Future research should thus focus on achieving breakthroughs in the elucidation of specific molecular mechanisms, rational drug design, and clinical research. Financial support and sponsorship This study was supported by the Shaanxi Key Science and Technology Plan Project (No. 2023-ZDLSF-26) and National Natural Science Foundation of China (Nos. 82474062 and 82274079). Author contributions Pang SD: Investigation, writing—original draft. Vaziri ND: Methodology, supervision, writing—review and editing. Zhao YY: Conceptualization, methodology, funding acquisition, writing—original draft, writing—review and editing. All authors have read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Conflict of interest Yingyong Zhao is an editorial board member of the journal. However, the article was subject to the journal’s standard procedures, with peer review handled independently of the editor and the affiliated research groups. Use of large language models, AI and machine learning tools None declared. Data availability statement Not applicable.