Klf2 Is an Essential Regulator of Vascular Hemodynamic Forces In Vivo

Lee, John S.; Yu, Qing; Shin, Jordan T.; Sebzda, Eric; Bertozzi, Cara C.; Chen, Mei; Mericko, Patti; Stadtfeld, Matthias; Zhou, Di; Cheng, Lan; Graf, Thomas; MacRae, Calum A.; Lepore, John J.; Lo, Cecilia; Kahn, Mark L.

doi:10.1016/j.devcel.2006.09.006

Cited by 258 publications

(281 citation statements)

References 46 publications

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“…Klf2 fl/fl mice were generated as previously described (40). SMURF1 gene-targeted mice (41) were obtained from the laboratory of Ying E. Zhang (Center for Cancer Research, National Cancer Institute, Bethesda, MD).…”

Section: Methodsmentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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Section: Methodsmentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Because there are no glomerular endothelial cellespecific Cre mice available, we generated global endothelial celle specific Klf2 knockout mice by crossing the Klf2 floxed mice 25 with VE-cadherin promoter driven Cre transgenic mice (VEC-Cre). Because Klf2 fl/fl ;VEC-Cre homozygous mice die embryonically, 25 Klf2 fl/þ ;VEC-Cre heterozygous knockout and Klf2 þ/þ ;VEC-Cre wild-type littermate control mice (hereafter referred as KO and WT, respectively) were used in our study.…”

Section: Generation Of Endothelial Cellespecific Klf2 Heterozygous Knmentioning

confidence: 99%

“…Because Klf2 fl/fl ;VEC-Cre homozygous mice die embryonically, 25 Klf2 fl/þ ;VEC-Cre heterozygous knockout and Klf2 þ/þ ;VEC-Cre wild-type littermate control mice (hereafter referred as KO and WT, respectively) were used in our study. KO mice were viable, fertile, and grossly normal.…”

Section: Generation Of Endothelial Cellespecific Klf2 Heterozygous Knmentioning

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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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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“…Klf2 fl/fl mice were generated as previously described (53). Lck-cre, scid, and Rag −/− γc −/− mice were purchased from Taconic, and Foxp3-cre and CCR7 −/− mice were purchased from Jackson Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.

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Klf2 Is an Essential Regulator of Vascular Hemodynamic Forces In Vivo

Cited by 258 publications

References 46 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

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

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

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