Role of Krüppel-Like Transcription Factors in Endothelial Biology

Atkins, G. Brandon; Jain, Mukesh K.

doi:10.1161/01.res.0000267856.00713.0a

Cited by 372 publications

(341 citation statements)

References 117 publications

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“…26 KLF2 has multiple binding sites in the promoter of nitric oxide synthase-3 (NOS3), 16,27 which encodes endothelial nitric oxide synthase (eNOS). Previous studies suggest a critical role of eNOS in the progression of kidney disease.…”

Section: Reduced Klf2 Expression Results In Increased Glomerular Endomentioning

confidence: 99%

“…Glomerular hyperfiltration causes shear stress in endothelial cells, 32 which is known to increase KLF2 expression. 26 Recently, we reported that reduced KLF2 expression in endothelial cells leads to more severe glomerular endothelial cell injury and kidney damage in early diabetic nephropathy, which is characterized by glomerular hyperfiltration. 18 However, we were unable to assess the relationship between hyperfiltration and KLF2 expression in diabetic mice, because KLF2 expression is also affected by high glucose and insulin.…”

Section: Discussionmentioning

confidence: 99%

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Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Zhong

Mallipattu

Estrada

et al. 2016

The American Journal of Pathology

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Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stresseinducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cellespecific Klf2 heterozygous knockout mice (KO) and their wild-type littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas KO-UNX mice did not. KO-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in KO-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.

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Section: Reduced Klf2 Expression Results In Increased Glomerular Endomentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Zhong

Mallipattu

Estrada

et al. 2016

The American Journal of Pathology

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“…Kruppel‐like factor 2 (KLF2) is a zinc‐finger transcription factor preferentially expressed in vascular endothelium, lung, and lymphocytes 1, 4, 5. It functions as a master regulator to maintain endothelial homeostasis5 and control multiple genes critical for anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells (ECs) 1, 4, 5, 6, 7, 8, 9, 10.…”

mentioning

confidence: 99%

“…It functions as a master regulator to maintain endothelial homeostasis5 and control multiple genes critical for anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells (ECs) 1, 4, 5, 6, 7, 8, 9, 10. For example, KLF2 potently induces the expression of vasodilatory and anti‐inflammatory genes such as endothelial nitric oxide synthase, inhibits vasoconstrictive factors such as endothelin‐1 expression, and represses expression of adhesion molecules, such as vascular cell adhesion molecule 1 (VCAM1) 1, 8, 10.…”

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confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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“…The Kruppel-like family of zinc finger genes is characterized by Cys2-His2 zinc fingers and can be divided further into subsets based on other structural features, including a seven-amino acid H/C link between adjacent fingers and several conserved NH2-terminal modules (19). The PRDM family was first identified when a homologous N-terminal 100-amino acid region (PR domain) was recognized as shared by RIZ (retinoblastoma protein-interacting zinc finger; PRDM2) and the PRDI-BF1/BLIMP1 transcription repressor (PRDM1) that promotes B lymphocyte maturation (20).…”

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confidence: 99%

Variety is the splice of life

Hamik

Jain

2008

Journal of Molecular and Cellular Cardiology

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The circulatory system is the first functioning organ system to develop in vertebrate embryos, and for mammalian embryos its function is critical for early embryo survival (1). Coordinated development of the heart, the blood vessels, and the blood requires close communication among the cells making up the different components (2), with nuclear events constituting the final common pathway of the networks that determine cell function and phenotype. During development in particular, the precise control of spatial and temporal expression of mRNAs and their protein products is required for successful system formation.Regulation of transcription factor (TF) activity is integral for this precision. Numerous studies have demonstrated lethal consequences of loss, abnormal function, or dysregulation of the temporal and cell-specific activity of TFs during vascular development (3,4). Precise regulation of TF activity can be achieved by alterations at several levels, including chromatin modifications, the concomitant presence of co-activating or inhibitory proteins, and regulation of expression of the TF itself, to name a few. Of the various mechanisms, regulation of TF expression via alternative splicing provides a potent source for precise regulation by generating a large number of protein products, from a single gene, that can have unique temporal-and tissue-specific functions.

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Role of Krüppel-Like Transcription Factors in Endothelial Biology

Cited by 372 publications

References 117 publications

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Variety is the splice of life

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