Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury
Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-bin...
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| Vydáno v: | Journal of the American Society of Nephrology Ročník 29; číslo 2; s. 492 |
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| Hlavní autoři: | , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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01.02.2018
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| ISSN: | 1533-3450, 1533-3450 |
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| Abstract | Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury. |
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| AbstractList | Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury. Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury. |
| Author | Salimi, Shabnam Lee-Kwon, Whaseon Lee, Hwan Hee Mitchell, Braxton D Lee, Jun Ho Choi, Soo Youn Parsa, Afshin Kwon, Hyug Moo Lim, Sun Woo Sanada, Satoru Yoo, Eun Jin |
| Author_xml | – sequence: 1 givenname: Soo Youn orcidid: 0000-0002-3149-5590 surname: Choi fullname: Choi, Soo Youn organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea – sequence: 2 givenname: Sun Woo surname: Lim fullname: Lim, Sun Woo organization: Transplantation Research Center, Catholic University of Korea, Seoul, Republic of Korea – sequence: 3 givenname: Shabnam surname: Salimi fullname: Salimi, Shabnam organization: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and – sequence: 4 givenname: Eun Jin surname: Yoo fullname: Yoo, Eun Jin organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea – sequence: 5 givenname: Whaseon surname: Lee-Kwon fullname: Lee-Kwon, Whaseon organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea – sequence: 6 givenname: Hwan Hee surname: Lee fullname: Lee, Hwan Hee organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea – sequence: 7 givenname: Jun Ho surname: Lee fullname: Lee, Jun Ho organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea – sequence: 8 givenname: Braxton D surname: Mitchell fullname: Mitchell, Braxton D organization: Geriatrics Research and Education Clinical Center and – sequence: 9 givenname: Satoru surname: Sanada fullname: Sanada, Satoru organization: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and – sequence: 10 givenname: Afshin surname: Parsa fullname: Parsa, Afshin email: hmkwon@unist.ac.kr, aparsa@medicine.umaryland.edu organization: Division of Nephrology, Department of Medicine, Baltimore Veterans Administration Medical Center, Baltimore, Maryland – sequence: 11 givenname: Hyug Moo surname: Kwon fullname: Kwon, Hyug Moo email: hmkwon@unist.ac.kr, aparsa@medicine.umaryland.edu organization: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea; hmkwon@unist.ac.kr aparsa@medicine.umaryland.edu |
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| SubjectTerms | Animals Blood Pressure - genetics Cell Movement Diabetes Mellitus - chemically induced Diabetic Nephropathies - etiology Diabetic Nephropathies - genetics Diabetic Nephropathies - pathology Gene Expression Glomerular Filtration Rate - genetics Haploinsufficiency Humans Hyperglycemia - complications Inflammation - etiology Inflammation - genetics Inflammation - pathology Macrophage Activation - genetics Macrophages - pathology Macrophages - physiology Mice Nitric Oxide Synthase Type III - genetics Polymorphism, Single Nucleotide Renal Insufficiency, Chronic - etiology Renal Insufficiency, Chronic - genetics Renal Insufficiency, Chronic - pathology Streptozocin Transcription Factors - genetics |
| Title | Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury |
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