Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice
Abstract Western-style diets, which are abundant in advanced glycation end products (AGEs), particularly methylglyoxal-derived AGE4, have been identified as contributing factors to the progression of diabetic kidney disease. The objective of this study was to elucidate the pathogenic mechanisms of A...
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SpringerOpen
2025-07-01
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| Series: | Applied Biological Chemistry |
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| Online Access: | https://doi.org/10.1186/s13765-025-01011-y |
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| author | Hee-Weon Lee Min Ji Gu Donghwan Kim Eun Hee Han Yoonsook Kim Sang Keun Ha |
| author_facet | Hee-Weon Lee Min Ji Gu Donghwan Kim Eun Hee Han Yoonsook Kim Sang Keun Ha |
| author_sort | Hee-Weon Lee |
| collection | DOAJ |
| description | Abstract Western-style diets, which are abundant in advanced glycation end products (AGEs), particularly methylglyoxal-derived AGE4, have been identified as contributing factors to the progression of diabetic kidney disease. The objective of this study was to elucidate the pathogenic mechanisms of AGE4 in renal injury via the NOX4/Nrf2/NLRP3 inflammasome pathway. AGE4 was administered to diabetic db/db mice to evaluate renal histopathology, mitochondrial dysfunction, and oxidative stress. Concurrently, mouse tubular kidney proximal cells (TKPTS) were subjected to transfection with RAGE small interfering RNA (siRNA) and treatment with AGE4 to evaluate molecular alterations in vitro. Histological and functional deterioration of the kidney in db/db mice was observed following AGE4 exposure, accompanied by upregulation of NOX4 and RAGE, and disrupted mitochondrial integrity. Notably, AGE4 activated NLRP3 inflammasome components, including NLRP3, ASC, Caspase-1, and IL-1β, indicating enhanced inflammatory signaling. In vitro results confirmed these findings, showing that RAGE knockdown suppressed AGE4-induced NOX4/Nrf2/NLRP3 inflammasome activation and mitigated mitochondrial damage. These findings demonstrate that AGE4 promotes oxidative stress and inflammation through RAGE-mediated NOX4/Nrf2/NLRP3 inflammasome signaling, contributing to diabetic kidney disease pathogenesis. This study underscores a novel mechanism of AGE4-induced renal injury and emphasizes its potential as a therapeutic target in diabetic nephropathy. |
| format | Article |
| id | doaj-art-36257d08021e4dfc9ef8fe22752b1cda |
| institution | Kabale University |
| issn | 2468-0842 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | SpringerOpen |
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| series | Applied Biological Chemistry |
| spelling | doaj-art-36257d08021e4dfc9ef8fe22752b1cda2025-08-20T03:46:21ZengSpringerOpenApplied Biological Chemistry2468-08422025-07-0168111410.1186/s13765-025-01011-yEffect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db miceHee-Weon Lee0Min Ji Gu1Donghwan Kim2Eun Hee Han3Yoonsook Kim4Sang Keun Ha5Korea Food Research InstituteKorea Food Research InstituteKorea Food Research InstituteBiopharmaceutical Research Center, Ochang Institute of Biological and Environmental Science, Korea Basic Science InstituteKorea Food Research InstituteKorea Food Research InstituteAbstract Western-style diets, which are abundant in advanced glycation end products (AGEs), particularly methylglyoxal-derived AGE4, have been identified as contributing factors to the progression of diabetic kidney disease. The objective of this study was to elucidate the pathogenic mechanisms of AGE4 in renal injury via the NOX4/Nrf2/NLRP3 inflammasome pathway. AGE4 was administered to diabetic db/db mice to evaluate renal histopathology, mitochondrial dysfunction, and oxidative stress. Concurrently, mouse tubular kidney proximal cells (TKPTS) were subjected to transfection with RAGE small interfering RNA (siRNA) and treatment with AGE4 to evaluate molecular alterations in vitro. Histological and functional deterioration of the kidney in db/db mice was observed following AGE4 exposure, accompanied by upregulation of NOX4 and RAGE, and disrupted mitochondrial integrity. Notably, AGE4 activated NLRP3 inflammasome components, including NLRP3, ASC, Caspase-1, and IL-1β, indicating enhanced inflammatory signaling. In vitro results confirmed these findings, showing that RAGE knockdown suppressed AGE4-induced NOX4/Nrf2/NLRP3 inflammasome activation and mitigated mitochondrial damage. These findings demonstrate that AGE4 promotes oxidative stress and inflammation through RAGE-mediated NOX4/Nrf2/NLRP3 inflammasome signaling, contributing to diabetic kidney disease pathogenesis. This study underscores a novel mechanism of AGE4-induced renal injury and emphasizes its potential as a therapeutic target in diabetic nephropathy.https://doi.org/10.1186/s13765-025-01011-yAdvanced glycation end productsMethylglyoxal-derived AGEsDiabetic kidney diseasesInflammasomeOxidative stress |
| spellingShingle | Hee-Weon Lee Min Ji Gu Donghwan Kim Eun Hee Han Yoonsook Kim Sang Keun Ha Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice Applied Biological Chemistry Advanced glycation end products Methylglyoxal-derived AGEs Diabetic kidney diseases Inflammasome Oxidative stress |
| title | Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice |
| title_full | Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice |
| title_fullStr | Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice |
| title_full_unstemmed | Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice |
| title_short | Effect of advanced glycation end products formed methylglyoxal, a food-borne dicarbonyl precursor, on the exacerbation of diabetic kidney disease by NOX4/Nrf2/NLRP3 inflammasome signaling pathway in db/db mice |
| title_sort | effect of advanced glycation end products formed methylglyoxal a food borne dicarbonyl precursor on the exacerbation of diabetic kidney disease by nox4 nrf2 nlrp3 inflammasome signaling pathway in db db mice |
| topic | Advanced glycation end products Methylglyoxal-derived AGEs Diabetic kidney diseases Inflammasome Oxidative stress |
| url | https://doi.org/10.1186/s13765-025-01011-y |
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