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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Veröffentlicht in:Journal of the American Society of Nephrology Jg. 29; H. 2; S. 492
Hauptverfasser: Choi, Soo Youn, Lim, Sun Woo, Salimi, Shabnam, Yoo, Eun Jin, Lee-Kwon, Whaseon, Lee, Hwan Hee, Lee, Jun Ho, Mitchell, Braxton D, Sanada, Satoru, Parsa, Afshin, Kwon, Hyug Moo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.02.2018
Schlagworte:
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
genetic variants
blood pressure
Diabetic nephropathy
chronic kidney disease
macrophages
ISSN:1533-3450, 1533-3450
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Zusammenfassung: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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ISSN:1533-3450
1533-3450
DOI:10.1681/ASN.2017070718