Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy
Hyperuricemia is an independent risk factor for chronic kidney disease and contributes to renal fibrosis. This study aims to investigate the effect of Src family kinase (SFK) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN, feeding ra...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1352730/full |
| _version_ | 1797254031316353024 |
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| author | Chongxiang Xiong Jin Deng Xin Wang Qidi Hou Shougang Zhuang Shougang Zhuang |
| author_facet | Chongxiang Xiong Jin Deng Xin Wang Qidi Hou Shougang Zhuang Shougang Zhuang |
| author_sort | Chongxiang Xiong |
| collection | DOAJ |
| description | Hyperuricemia is an independent risk factor for chronic kidney disease and contributes to renal fibrosis. This study aims to investigate the effect of Src family kinase (SFK) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN, feeding rats a mixture of adenine and potassium oxonate increased Src phosphorylation, severe glomerular sclerosis, and renal interstitial fibrosis, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of PP1, a highly selective SFK inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. PP1 treatment also inhibited hyperuricemia-induced activation of the TGF-β1/Smad3, STAT3, ERK1/2, and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, PP1 treatment significantly reduced serum uric acid levels and xanthine oxidase activity. Thus, blocking Src can attenuate development of HN via a mechanism associated with the suppression of TGF-β1 signaling, inflammation, and uric acid production. The results suggest that Src inhibition might be a promising therapeutic strategy for HN. |
| first_indexed | 2024-04-24T21:43:29Z |
| format | Article |
| id | doaj.art-438d76b9ee5648bf82b794c783458f60 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-24T21:43:29Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-438d76b9ee5648bf82b794c783458f602024-03-21T04:48:34ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13527301352730Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathyChongxiang Xiong0Jin Deng1Xin Wang2Qidi Hou3Shougang Zhuang4Shougang Zhuang5Department of Nephrology, The First Affiliated Hospital of Dongguan, Guangdong Medical University, Dongguan, Guangdong, ChinaDepartment of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of Dongguan, Guangdong Medical University, Dongguan, Guangdong, ChinaDepartment of Nephrology, The First Affiliated Hospital of Dongguan, Guangdong Medical University, Dongguan, Guangdong, ChinaDepartment of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, United StatesDepartment of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaHyperuricemia is an independent risk factor for chronic kidney disease and contributes to renal fibrosis. This study aims to investigate the effect of Src family kinase (SFK) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN, feeding rats a mixture of adenine and potassium oxonate increased Src phosphorylation, severe glomerular sclerosis, and renal interstitial fibrosis, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of PP1, a highly selective SFK inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. PP1 treatment also inhibited hyperuricemia-induced activation of the TGF-β1/Smad3, STAT3, ERK1/2, and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, PP1 treatment significantly reduced serum uric acid levels and xanthine oxidase activity. Thus, blocking Src can attenuate development of HN via a mechanism associated with the suppression of TGF-β1 signaling, inflammation, and uric acid production. The results suggest that Src inhibition might be a promising therapeutic strategy for HN.https://www.frontiersin.org/articles/10.3389/fphar.2024.1352730/fullhyperuricemiahyperuricemic nephropathySrc family kinasesSrcfibrosiskidney |
| spellingShingle | Chongxiang Xiong Jin Deng Xin Wang Qidi Hou Shougang Zhuang Shougang Zhuang Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy Frontiers in Pharmacology hyperuricemia hyperuricemic nephropathy Src family kinases Src fibrosis kidney |
| title | Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy |
| title_full | Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy |
| title_fullStr | Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy |
| title_full_unstemmed | Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy |
| title_short | Pharmacological inhibition of Src family kinases attenuates hyperuricemic nephropathy |
| title_sort | pharmacological inhibition of src family kinases attenuates hyperuricemic nephropathy |
| topic | hyperuricemia hyperuricemic nephropathy Src family kinases Src fibrosis kidney |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1352730/full |
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