Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease
Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with dis...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/9/783 |
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| author | Bowen Sun Xifan Wang Xiaoxue Liu Longjiao Wang Fazheng Ren Xiaoyu Wang Xiaojing Leng |
| author_facet | Bowen Sun Xifan Wang Xiaoxue Liu Longjiao Wang Fazheng Ren Xiaoyu Wang Xiaojing Leng |
| author_sort | Bowen Sun |
| collection | DOAJ |
| description | Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD. |
| first_indexed | 2024-03-10T16:53:28Z |
| format | Article |
| id | doaj.art-f896002497874ede964d2d6fc14cd742 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T16:53:28Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-f896002497874ede964d2d6fc14cd7422023-11-20T11:14:40ZengMDPI AGAntioxidants2076-39212020-08-019978310.3390/antiox9090783Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney DiseaseBowen Sun0Xifan Wang1Xiaoxue Liu2Longjiao Wang3Fazheng Ren4Xiaoyu Wang5Xiaojing Leng6Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaKey Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, ChinaChronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD.https://www.mdpi.com/2076-3921/9/9/783hippuric acidprotein-bound uremic toxinrenal fibrosisoxidative stressantioxidationNRF2 |
| spellingShingle | Bowen Sun Xifan Wang Xiaoxue Liu Longjiao Wang Fazheng Ren Xiaoyu Wang Xiaojing Leng Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease Antioxidants hippuric acid protein-bound uremic toxin renal fibrosis oxidative stress antioxidation NRF2 |
| title | Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease |
| title_full | Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease |
| title_fullStr | Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease |
| title_full_unstemmed | Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease |
| title_short | Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease |
| title_sort | hippuric acid promotes renal fibrosis by disrupting redox homeostasis via facilitation of nrf2 keap1 cul3 interactions in chronic kidney disease |
| topic | hippuric acid protein-bound uremic toxin renal fibrosis oxidative stress antioxidation NRF2 |
| url | https://www.mdpi.com/2076-3921/9/9/783 |
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