Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice
Abstract Background Recently, clinical studies have shown the protective effects of sodium glucose co-transporter2 (SGLT2) inhibitors against progression of diabetic nephropathy, but the underlying molecular mechanisms remain unclear. Methods Diabetic mice were prepared by injecting nicotinamide and...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Diabetology & Metabolic Syndrome |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13098-019-0454-6 |
| _version_ | 1819087283137019904 |
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| author | Masa-Ki Inoue Yasuka Matsunaga Yusuke Nakatsu Takeshi Yamamotoya Koji Ueda Akifumi Kushiyama Hideyuki Sakoda Midori Fujishiro Hiraku Ono Misaki Iwashita Tomomi Sano Fusanori Nishimura Kenichi Morii Kensuke Sasaki Takao Masaki Tomoichiro Asano |
| author_facet | Masa-Ki Inoue Yasuka Matsunaga Yusuke Nakatsu Takeshi Yamamotoya Koji Ueda Akifumi Kushiyama Hideyuki Sakoda Midori Fujishiro Hiraku Ono Misaki Iwashita Tomomi Sano Fusanori Nishimura Kenichi Morii Kensuke Sasaki Takao Masaki Tomoichiro Asano |
| author_sort | Masa-Ki Inoue |
| collection | DOAJ |
| description | Abstract Background Recently, clinical studies have shown the protective effects of sodium glucose co-transporter2 (SGLT2) inhibitors against progression of diabetic nephropathy, but the underlying molecular mechanisms remain unclear. Methods Diabetic mice were prepared by injecting nicotinamide and streptozotocin, followed by high-sucrose diet feeding (NA/STZ/Suc mice). The SGLT2 inhibitor canagliflozin was administered as a 0.03% (w/w) mixture in the diet for 4 weeks. Then, various parameters and effects of canagliflozin on diabetic nephropathy were investigated. Results Canagliflozin administration to NA/STZ/Suc mice normalized hyperglycemia as well as elevated renal mRNA of collagen 1a1, 1a2, CTGF, TNFα and MCP-1. Microscopic observation revealed reduced fibrotic deposition in the kidneys of canagliflozin-treated NA/STZ/Suc mice. Interestingly, the protein level of Pin1, reportedly involved in the inflammation and fibrosis affecting several tissues, was markedly increased in the NA/STZ/Suc mouse kidney, but this was normalized with canagliflozin treatment. The cells showing increased Pin1 expression in the kidney were mainly mesangial cells, along with podocytes, based on immunohistochemical analysis. Furthermore, it was revealed that canagliflozin induced AMP-activated kinase (AMPK) activation concentration-dependently in CRL1927 mesangial as well as THP-1 macrophage cell lines. AMPK activation was speculated to suppress mesangial cell proliferation and exert anti-inflammatory effects in hematopoietic cells. Conclusion Therefore, we can reasonably suggest that normalized Pin1 expression and AMPK activation contribute to the molecular mechanisms underlying SGLT2 inhibitor-induced suppression of diabetic nephropathy, possibly at least in part by reducing inflammation and fibrotic change. |
| first_indexed | 2024-12-21T21:33:41Z |
| format | Article |
| id | doaj.art-edc74bd8d48b4a0db299cb038e0d9226 |
| institution | Directory Open Access Journal |
| issn | 1758-5996 |
| language | English |
| last_indexed | 2024-12-21T21:33:41Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj.art-edc74bd8d48b4a0db299cb038e0d92262022-12-21T18:49:33ZengBMCDiabetology & Metabolic Syndrome1758-59962019-07-0111111110.1186/s13098-019-0454-6Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in miceMasa-Ki Inoue0Yasuka Matsunaga1Yusuke Nakatsu2Takeshi Yamamotoya3Koji Ueda4Akifumi Kushiyama5Hideyuki Sakoda6Midori Fujishiro7Hiraku Ono8Misaki Iwashita9Tomomi Sano10Fusanori Nishimura11Kenichi Morii12Kensuke Sasaki13Takao Masaki14Tomoichiro Asano15Department of Medical Science, Graduate School of Medicine, University of HiroshimaCenter for Translational Research in Infection & Inflammation, School of Medicine, Tulane UniversityDepartment of Medical Science, Graduate School of Medicine, University of HiroshimaDepartment of Medical Science, Graduate School of Medicine, University of HiroshimaDepartment of Medical Science, Graduate School of Medicine, University of HiroshimaDivision of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life FoundationDivision of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of MiyazakiDivision of Diabetes and Metabolic Diseases, Nihon University School of MedicineDepartment of Clinical Cell Biology, Graduate School of Medicine, Chiba UniversitySection of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, FukuokaSection of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, FukuokaSection of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, FukuokaDepartment of Nephrology, Hiroshima University HospitalDepartment of Nephrology, Hiroshima University HospitalDepartment of Nephrology, Hiroshima University HospitalDepartment of Medical Science, Graduate School of Medicine, University of HiroshimaAbstract Background Recently, clinical studies have shown the protective effects of sodium glucose co-transporter2 (SGLT2) inhibitors against progression of diabetic nephropathy, but the underlying molecular mechanisms remain unclear. Methods Diabetic mice were prepared by injecting nicotinamide and streptozotocin, followed by high-sucrose diet feeding (NA/STZ/Suc mice). The SGLT2 inhibitor canagliflozin was administered as a 0.03% (w/w) mixture in the diet for 4 weeks. Then, various parameters and effects of canagliflozin on diabetic nephropathy were investigated. Results Canagliflozin administration to NA/STZ/Suc mice normalized hyperglycemia as well as elevated renal mRNA of collagen 1a1, 1a2, CTGF, TNFα and MCP-1. Microscopic observation revealed reduced fibrotic deposition in the kidneys of canagliflozin-treated NA/STZ/Suc mice. Interestingly, the protein level of Pin1, reportedly involved in the inflammation and fibrosis affecting several tissues, was markedly increased in the NA/STZ/Suc mouse kidney, but this was normalized with canagliflozin treatment. The cells showing increased Pin1 expression in the kidney were mainly mesangial cells, along with podocytes, based on immunohistochemical analysis. Furthermore, it was revealed that canagliflozin induced AMP-activated kinase (AMPK) activation concentration-dependently in CRL1927 mesangial as well as THP-1 macrophage cell lines. AMPK activation was speculated to suppress mesangial cell proliferation and exert anti-inflammatory effects in hematopoietic cells. Conclusion Therefore, we can reasonably suggest that normalized Pin1 expression and AMPK activation contribute to the molecular mechanisms underlying SGLT2 inhibitor-induced suppression of diabetic nephropathy, possibly at least in part by reducing inflammation and fibrotic change.http://link.springer.com/article/10.1186/s13098-019-0454-6Diabetes mellitusNephropathySGLT2 inhibitorCanagliflozinAMPKPin1 |
| spellingShingle | Masa-Ki Inoue Yasuka Matsunaga Yusuke Nakatsu Takeshi Yamamotoya Koji Ueda Akifumi Kushiyama Hideyuki Sakoda Midori Fujishiro Hiraku Ono Misaki Iwashita Tomomi Sano Fusanori Nishimura Kenichi Morii Kensuke Sasaki Takao Masaki Tomoichiro Asano Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice Diabetology & Metabolic Syndrome Diabetes mellitus Nephropathy SGLT2 inhibitor Canagliflozin AMPK Pin1 |
| title | Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice |
| title_full | Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice |
| title_fullStr | Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice |
| title_full_unstemmed | Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice |
| title_short | Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice |
| title_sort | possible involvement of normalized pin1 expression level and ampk activation in the molecular mechanisms underlying renal protective effects of sglt2 inhibitors in mice |
| topic | Diabetes mellitus Nephropathy SGLT2 inhibitor Canagliflozin AMPK Pin1 |
| url | http://link.springer.com/article/10.1186/s13098-019-0454-6 |
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