Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its...
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MDPI AG
2024-03-01
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| author | Ewud Agborbesong Julie Xia Zhou Hongbing Zhang Linda Xiaoyan Li Peter C. Harris James P. Calvet Xiaogang Li |
| author_facet | Ewud Agborbesong Julie Xia Zhou Hongbing Zhang Linda Xiaoyan Li Peter C. Harris James P. Calvet Xiaogang Li |
| author_sort | Ewud Agborbesong |
| collection | DOAJ |
| description | Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in <i>PKD1</i> mutant mouse and human ADPKD kidneys. Genetic knockout of <i>SMYD3</i> in a <i>PKD1</i> knockout mouse model delayed cyst growth and improved kidney function compared with <i>PKD1</i> single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in <i>PKD1</i> mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in <i>PKD1</i> mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD. |
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| last_indexed | 2024-04-24T18:31:09Z |
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| spelling | doaj.art-5c55ec817551433eaf550eaa1e543d532024-03-27T13:22:55ZengMDPI AGBiomedicines2227-90592024-03-0112360310.3390/biomedicines12030603Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome InstabilityEwud Agborbesong0Julie Xia Zhou1Hongbing Zhang2Linda Xiaoyan Li3Peter C. Harris4James P. Calvet5Xiaogang Li6Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USAAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in <i>PKD1</i> mutant mouse and human ADPKD kidneys. Genetic knockout of <i>SMYD3</i> in a <i>PKD1</i> knockout mouse model delayed cyst growth and improved kidney function compared with <i>PKD1</i> single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in <i>PKD1</i> mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in <i>PKD1</i> mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.https://www.mdpi.com/2227-9059/12/3/603nephrologyADPKDepigeneticsSMYD3genome instability |
| spellingShingle | Ewud Agborbesong Julie Xia Zhou Hongbing Zhang Linda Xiaoyan Li Peter C. Harris James P. Calvet Xiaogang Li Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability Biomedicines nephrology ADPKD epigenetics SMYD3 genome instability |
| title | Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability |
| title_full | Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability |
| title_fullStr | Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability |
| title_full_unstemmed | Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability |
| title_short | Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability |
| title_sort | overexpression of smyd3 promotes autosomal dominant polycystic kidney disease by mediating cell proliferation and genome instability |
| topic | nephrology ADPKD epigenetics SMYD3 genome instability |
| url | https://www.mdpi.com/2227-9059/12/3/603 |
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