Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress
Background/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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Cell Physiol Biochem Press GmbH & Co KG
2018-03-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | https://www.karger.com/Article/FullText/488404 |
| _version_ | 1819019055870246912 |
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| author | Dong Huang Mei-ling Yan Kan-kai Chen Rong Sun Zhi-feng Dong Peng-long Wu Shuai Li Guang-shuo Zhu Shi-xin Ma Ye-sheng Pan Jing-wei Pan Wei Zhu Jun Xu Meng Wei Jing-bo Li |
| author_facet | Dong Huang Mei-ling Yan Kan-kai Chen Rong Sun Zhi-feng Dong Peng-long Wu Shuai Li Guang-shuo Zhu Shi-xin Ma Ye-sheng Pan Jing-wei Pan Wei Zhu Jun Xu Meng Wei Jing-bo Li |
| author_sort | Dong Huang |
| collection | DOAJ |
| description | Background/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. Methods: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. Results: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-β expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. Conclusions: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress. |
| first_indexed | 2024-12-21T03:29:14Z |
| format | Article |
| id | doaj.art-494767a835c94d5e8e85f242d93b0dcb |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-21T03:29:14Z |
| publishDate | 2018-03-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-494767a835c94d5e8e85f242d93b0dcb2022-12-21T19:17:31ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-03-0146192210.1159/000488404488404Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum StressDong HuangMei-ling YanKan-kai ChenRong SunZhi-feng DongPeng-long WuShuai LiGuang-shuo ZhuShi-xin MaYe-sheng PanJing-wei PanWei ZhuJun XuMeng WeiJing-bo LiBackground/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. Methods: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. Results: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-β expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. Conclusions: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.https://www.karger.com/Article/FullText/488404Cardiorenal syndromeGenetically Altered and Transgenic ModelsMyocardial InfarctionNephrology and KidneyRemodeling |
| spellingShingle | Dong Huang Mei-ling Yan Kan-kai Chen Rong Sun Zhi-feng Dong Peng-long Wu Shuai Li Guang-shuo Zhu Shi-xin Ma Ye-sheng Pan Jing-wei Pan Wei Zhu Jun Xu Meng Wei Jing-bo Li Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress Cellular Physiology and Biochemistry Cardiorenal syndrome Genetically Altered and Transgenic Models Myocardial Infarction Nephrology and Kidney Remodeling |
| title | Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress |
| title_full | Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress |
| title_fullStr | Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress |
| title_full_unstemmed | Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress |
| title_short | Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress |
| title_sort | cardiac specific overexpression of silent information regulator 1 protects against heart and kidney deterioration in cardiorenal syndrome via inhibition of endoplasmic reticulum stress |
| topic | Cardiorenal syndrome Genetically Altered and Transgenic Models Myocardial Infarction Nephrology and Kidney Remodeling |
| url | https://www.karger.com/Article/FullText/488404 |
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