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Qiu S.,Capital Medical University | Qiu S.,Key Laboratory of Remodeling related Cardiovascular Diseases | Qiu S.,Beijing Institute of Heart | Xiao Z.,Capital Medical University | And 19 more authors.
Journal of Pathology | Year: 2015

TGFβ1/Smad, Wnt/β-catenin and snail1 are preferentially activated in renal tubular epithelia after injury, leading to epithelial-mesenchymal transition (EMT). The stress response is coupled to EMT and kidney injury; however, the underlying mechanism of the stress response in EMT remains elusive. AMP-activated protein kinase (AMPK) signalling is responsive to stress and regulates cell energy balance and differentiation. We found that knockdown of AMPKα, especially AMPKα2, enhanced EMT by up-regulating β-catenin and Smad3 in vitro. AMPKα2 deficiency enhanced EMT and fibrosis in a murine unilateral ureteral obstruction (UUO) model. AMPKα2 deficiency also increased the expression of chemokines KC and MCP-1, along with enhanced infiltration of inflammatory cells into the kidney after UUO. CK2β interacted physically with AMPKα and enhanced AMPKα Thr172 phosphorylation and its catalytic activity. Thus, activated AMPKα signalling suppresses EMT and secretion of chemokines in renal tubular epithelia through interaction with CK2β to attenuate renal injury. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Xue H.,Tsinghua University | Xiao Z.,Capital Medical University | Xiao Z.,Key Laboratory of Remodeling related Cardiovascular Diseases | Zhang J.,Capital Medical University | And 9 more authors.
Journal of Biological Chemistry | Year: 2013

Wnt/β-catenin signaling plays key roles in embryonic development and tissue homeostasis. Dapper3/Dact3, one of the three members of the Dapper gene family, is transcriptionally repressed in colorectal cancer and may function as a negative regulator of Wnt/β-catenin signaling. To investigate its physiological functions, we generated a mouse strain harboring conditional null alleles of Dapper3 (Dapper3flox/flox), and homozygous Dapper3-deficient (Dapper3-/-) mice were produced after crossing with EIIa-cre transgenic mice. We found that Dapper3 is not essential for mouse embryogenesis, postnatal survival, and reproduction. However, adult Dapper3 -/- mice exhibited a mild reduction in body weight compared with their wild-type littermates, suggesting a functional role of Dapper3 in postnatal growth. To investigate the role of Dapper3 in renal fibrosis, we employed the unilateral ureteral obstruction model. Dapper3 mRNA expression was up-regulated in kidney after unilateral ureteral obstruction. Loss of the Dapper3 gene enhanced myofibroblast activation and extracellular matrix overproduction in the obstructed kidney. Moreover, this aggravated fibrotic phenotype was accompanied with accumulation of Dishevelled2 and β-catenin proteins and activation of Wnt-targeted fibrotic genes. In primary renal tubular cells, Dapper3 inhibits Wnt-induced epithelial-to-mesenchymal transition. Consistently, Dapper3 interacted with and down-regulated Dishevelled2 protein and attenuated the Wnt-responsive Topflash reporter expression. These findings together suggest that Dapper3 antagonizes the fibrotic actions of Wnt signaling in kidney. © 2013 by The American Society for Biochemistry and Molecular Biology Inc.


Peng X.,Capital Medical University | Peng X.,Key Laboratory of Remodeling Related Cardiovascular Diseases | Peng X.,Nanchang University | Zhang J.,Capital Medical University | And 7 more authors.
Journal of Immunology | Year: 2015

Chemokines modulate inflammatory responses that are prerequisites for kidney injury. The specific role of monocyte-associated CX3CR1 and its cognate ligand CX3CL1 in unilateral ureteral obstruction (UUO)-induced kidney injury remains unclear. In this study, we found that UUO caused a CCR2-dependent increase in numbers of Ly6Chi monocytes both in the blood and kidneys and of Ly6C-CX3CR1+ macrophages in the obstructed kidneys of mice. Using CX3CR1gfp/+ knockin mice, we observed a rapid conversion of infiltrating proinflammatory Ly6C+CX3CR11o monocytes/macrophages to anti-inflammatory Ly6C-CX3CR1hi macrophages. CX3CR1 deficiency affected neither monocyte trafficking nor macrophage differentiation in vivo upon renal obstruction, but CX3CR1 expression in monocytes and macrophages was required for increases in fibrosis in the obstructed kidneys. Mechanistically, CX3CL1-CX3CR1 interaction increases Ly6C-CX3CR1hi macrophage survival within the obstructed kidneys. Therefore, CX3CL1 and CX3CR1 may represent attractive therapeutic targets in obstructive nephropathy. © 2015 by The American Association of Immunologists, Inc.


Zhang C.,Capital Medical University | Li Y.,Capital Medical University | Wu Y.,Capital Medical University | Wang L.,Capital Medical University | And 3 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Interleukin-6 (IL-6), as a multifunctional cytokine, was involved in the inflammation microenvironment of muscle regeneration. Results: In mice lacking IL-6, less macrophage recruitment and decreased myoblast proliferation impairs muscle regeneration. Conclusion: In monocytes/macrophages, activation of the IL-6/STAT3 pathway is critical to macrophage migration and myoblast proliferation during muscle regeneration. Significance: IL-6/STAT3 pathway is essential for muscle regeneration. Inflammation and microenvironment play a crucial role in muscle regeneration. IL (interleukin)-6, as a multifunctional cytokine is involved in the processes. However, the causative effect of IL-6 in muscle regeneration remains unclear. In a mouse model of cardiotoxin-induced muscle injury/regeneration, infiltrated monocytes/ macrophages produce a high level of IL-6 started on 1 day (24 h) after injury. In IL-6 knock-out (/) mice, the muscle regeneration procedure was impaired along with decreased myogenic determination factor (MyoD) and myogenin mRNA level and increased interstitial fibrosis. The IL-6/ mice exhibited less macrophage infiltration, lower inflammatory cytokine (IL-1, inducible NO synthase, Transforming growth factor (TGF)-1, and IL-10) and chemokine (CCL2, CCL3, and CCL5) expression, and inhibited myoblast proliferation. In vitro, IL-6 deficiency or Signal Transducer and Activator of Transcription 3 (STAT3) knockdown in activated macrophage attenuated the expression of CCL2, CCL3, but not CCL5, which resulted in less macrophage migration. Moreover, inflammatory macrophages promoted myoblast proliferation in an IL-6-dependent manner. Finally, adoptive transfer IL-6/ BM cells into IL-6/ mice rescued the impaired regeneration with improved MyoD and myogenin expression. Taken together, IL-6 expression and the activated STAT3 signaling pathway in monocytes/ macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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