Insulin prevents pulmonary vascular leakage by inhibiting transglutaminase 2 in diabetic mice

Jeon, Hye‐Yoon; Seo, Jae-Ah; Jung, Se-Hui; Lee, Yeon-Ju; Han, Eun‐Taek; Park, Won Sun; Hong, Seok‐Ho; Kim, Young-Myeong; Ha, Kwon‐Soo

doi:10.1016/j.lfs.2019.116711

Cited by 7 publications

(9 citation statements)

References 29 publications

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“…19 Also, adventitial fibroblasts are well-documented to transdifferentiate into myofibroblasts identified by expression of the contractile protein α-smooth muscle actin. 44 These authors also report that TG2 deficiency prevents hyperglycemia-induced pulmonary vascular permeability in diabetic mice. Notably, high glucose media increased TG2 activity ( Figure 5B) and the expression of TG2 and glycolytic and fibrogenic markers in PA adventitial fibroblasts ( Figure 6).…”

Section: Discussionmentioning

confidence: 90%

“…Recently, Jeon et al demonstrated that insulin treatment attenuated high glucose-induced TG2 activation and signaling in pulmonary microvascular endothelial cells. 44 These authors also report that TG2 deficiency prevents hyperglycemia-induced pulmonary vascular permeability in diabetic mice. Taken together, these studies describe a role for high glucose-mediated TG2 activation in pulmonary vascular dysfunction.…”

Section: Discussionmentioning

confidence: 90%

“…Notably, high glucose media increased TG2 activity (Figure B) and the expression of TG2 and glycolytic and fibrogenic markers in PA adventitial fibroblasts (Figure ). Recently, Jeon et al demonstrated that insulin treatment attenuated high glucose‐induced TG2 activation and signaling in pulmonary microvascular endothelial cells . These authors also report that TG2 deficiency prevents hyperglycemia‐induced pulmonary vascular permeability in diabetic mice.…”

Section: Discussionmentioning

confidence: 91%

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Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose‐induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose‐induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis‐mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 91%

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Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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“…Actin filaments were visualized using Alexa Fluor 488 phalloidin (1:200; Thermo Fisher Scientific) as previously described [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Microalbuminuria is caused by disruption of the glomerular filtration barrier due to foot process effacement of podocytes, glomerular basement membrane (GBM) thickening, and microvascular dysfunction [ 3 , 8 ]. Notably, microvascular dysfunction plays a critical role in the pathogenesis of diabetic microvascular complications, such as diabetic retinopathy, neuropathy, and pulmonary disease [ 9 , 10 , 11 ]. In diabetic retinas and lungs, microvascular dysfunction results from hyperglycemia-induced elevation of vascular endothelial growth factor (VEGF) expression and subsequent disruption of vascular integrity and microvascular leakage [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Midazolam Ameliorates Hyperglycemia-Induced Glomerular Endothelial Dysfunction by Inhibiting Transglutaminase 2 in Diabetes

Seo

Sayyed

Lee

et al. 2022

IJMS

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Midazolam is an anesthetic widely used for anxiolysis and sedation; however, to date, a possible role for midazolam in diabetic kidney disease remains unknown. Here, we investigated the effect of midazolam on hyperglycemia-induced glomerular endothelial dysfunction and elucidated its mechanism of action in kidneys of diabetic mice and human glomerular microvascular endothelial cells (HGECs). We found that, in diabetic mice, subcutaneous midazolam treatment for 6 weeks attenuated hyperglycemia-induced elevation in urine albumin/creatinine ratios. It also ameliorated hyperglycemia-induced adherens junction disruption and subsequent microvascular leakage in glomeruli of diabetic mice. In HGECs, midazolam suppressed high glucose-induced vascular endothelial-cadherin disruption and endothelial cell permeability via inhibition of intracellular Ca2+ elevation and subsequent generation of reactive oxygen species (ROS) and transglutaminase 2 (TGase2) activation. Notably, midazolam also suppressed hyperglycemia-induced ROS generation and TGase2 activation in glomeruli of diabetic mice and markedly improved pathological alterations in glomerular ultrastructure in these animals. Analysis of kidneys from diabetic Tgm2−/− mice further revealed that TGase2 played a critical role in microvascular leakage. Overall, our findings indicate that midazolam ameliorates hyperglycemia-induced glomerular endothelial dysfunction by inhibiting ROS-mediated activation of TGase2.

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Polymer-Based Delivery of Peptide Drugs to Treat Diabetes: Normalizing Hyperglycemia and Preventing Diabetic Complications

Jeon

Lee

2022

BioChip J

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Diabetes is a serious metabolic disease in which chronic hyperglycemia results in diabetic microvascular and macrovascular complications from progressive vascular damage and dysfunction. Diabetes is life-threating and disabling, and is associated with costly complications and reduced life expectancy. Therefore, developing therapies for the treatment of diabetes is urgent and a significant challenge. Several peptides, including insulin, glucagon-like peptide-1, proinsulin C-peptide, and apelin, effectively normalize hyperglycemia and prevent hyperglycemia-induced diabetic complications, which are essential for the treatment of diabetes. However, a key limitation of peptide drugs for the clinical use is their short half-life. In this review, we describe the pathophysiological mechanisms and treatments of diabetic vascular complications. In addition, we discuss modification of peptide drugs by various approaches involving polymers to extend their blood circulating times and the use of the modified peptides in experimental and clinical studies.

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Insulin prevents pulmonary vascular leakage by inhibiting transglutaminase 2 in diabetic mice

Cited by 7 publications

References 29 publications

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Midazolam Ameliorates Hyperglycemia-Induced Glomerular Endothelial Dysfunction by Inhibiting Transglutaminase 2 in Diabetes

Polymer-Based Delivery of Peptide Drugs to Treat Diabetes: Normalizing Hyperglycemia and Preventing Diabetic Complications

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