A novel role for the chemokine receptor Cxcr4 in kidney morphogenesis: An in vitro study

Ueland, Joseph M.; Yuan, Amy; Marlier, Arnaud; Gallagher, Anna-Rachel; Karihaloo, Anil

doi:10.1002/dvdy.21943

Cited by 31 publications

(36 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[61][62][63] Potentially, such podocyte precursors of glomerular parietal epithelial cell origin may be involved in the repopulation of the glomerular tuft during podocyte injury. 58 -60,64 CXCR4/CXCL12 guide cell migration in a number of systems (eg, renal morphogenesis (tubulogenesis), neuron/ axon development, and tumor metastasis [65][66][67][68] ). Using an in vitro wound healing assay to evaluate CXCR4-dependent migration, we could demonstrate that treatment of cultured podocytes with a blocking CXCR4 antibody significantly impaired in vitro wound healing and hence CXCR4-dependent cell migration.…”

Section: Discussionmentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

show abstract

Section: Discussionmentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…In the presence of hepatocyte growth factor (HGF), MDCK and other epithelial cell types grown under 3D in vitro culture conditions are stimulated to undergo tubulogenesis (32,33,50,52). The mechanisms controlling the regulation of cystogenesis and tubulogenesis appear to be complex and dependent on both the nature and the composition of the growth environment.Chemokines and their receptors have recently been discovered to play a significant part in regulating epithelial cell morphology (22,35,(55)(56)(57). In 1987, Yoshimura and colleagues described interleukin-8 (IL-8) as the first inflammatory cytokine (65).…”

mentioning

confidence: 99%

“…Chemokines and their receptors have recently been discovered to play a significant part in regulating epithelial cell morphology (22,35,(55)(56)(57). In 1987, Yoshimura and colleagues described interleukin-8 (IL-8) as the first inflammatory cytokine (65).…”

mentioning

confidence: 99%

Epithelial morphogenesis of MDCK cells in three-dimensional collagen culture is modulated by interleukin-8

Wells

Yarborough

Lifton

et al. 2013

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Under these conditions, MDCK cells spontaneously formed either hollow spherical cysts or flat monolayer sheets, respectively. Microarray analysis of gene expression revealed a twofold or greater expression difference in 732 gene sets from MDCK cysts compared with monolayers (false discovery rate or FDR-adjusted P values Ͻ0.05). Interleukin-8 (IL-8) was reproducibly found to be among the genes whose expression was most dramatically upregulated, and this behavior was verified through real-time PCR analysis. The level of IL-8 protein expression was significantly increased in 3D MDCK cultures compared with that detected in cells in 2D culture. Hepatocyte growth factor (HGF) induces MDCK cells in 3D culture to form linear tubule-like structures. We found that HGF stimulation caused MDCK cells in 3D culture to decrease the expression of IL-8 at both the mRNA and protein levels. Furthermore, the addition of recombinant IL-8 to HGF-stimulated 3D MDCK cultures was sufficient to partially reverse the tubulogenic effects of HGF, resulting in the formation of cystic structures. These data suggest that IL-8 participates in the formation of cystic structures by MDCK cells in 3D culture and that HGF may stimulate tubulogenesis through the suppression of IL-8. renal epithelial cells; interleukin-8; hepatocyte growth factor; morphogenesis; Madin-Darby canine kidney IN TISSUES SUCH AS the lungs, intestines, and kidneys, epithelial cells form barriers between an organism and its external milieu. The surface membranes of these epithelial cells are exposed to disparate environments and are divided into discrete apical and basolateral domains (4,8,37,39). These membrane domains are established and maintained through the directed trafficking and selective retention of cellular components. In addition to this capacity to generate polarized plasma membrane domains with distinct biochemical and physiological properties, epithelial cells must also be able to organize themselves into complex multicellular architectures. The formation and maintenance of these structures is dependent both upon intercellular interactions between epithelial cells and upon cell-matrix interactions.Interactions between an individual cell and its surrounding environment are essential in the activation of signaling networks that subsequently regulate polarity and the determination of epithelial structural morphology (6,7,9,40,48). As epithelial cells establish polarity and interactions with their environment they can begin to function together to generate organized multicellular structures. This property is exemplified by comparing the behaviors of epithelial cell lines, such as Madin-Darby canine kidney (MDCK) cells, grown in twodimensional (2D) vs. three-dimensional (3D) culture conditions. MDCK cells form flat monolayer sheets when grown atop tissue culture plastic, permeable filter supports, and various extracellular matrix (ECM) substrates in traditional 2D culture conditions. When grown in 3D culture, in which cells are embedded within an ECM substrate, MDCK...

show abstract

“…A number of studies have shown that CXCR4 is one of the most comprehensive cytokine receptor that plays an important role in the growth and metastasis of a variety of malignant tumors (45). Strictly related to HCC, it was demonstrated that CXCR4 expression may be an independent risk factor for bone metastasis and associated with a poor clinical outcome (46).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma a retrospective clinico-pathologic and immunohistochemical study of 15 cases

Dumitrescu¹,

Dumitrescu²,

Cernea³

et al. 2013

Romanian Review of Laboratory Medicine

View full text Add to dashboard Cite

show abstract

A novel role for the chemokine receptor Cxcr4 in kidney morphogenesis: An in vitro study

Abstract: The CXCR4 chemokine receptor is involved in hematopoietic stem cell homing, neuronal development, and angiogenesis. We show a significant new role for this receptor in epithelial patterning and renal morphogenesis. This receptor is expressed in the ureteric bud (

Cited by 31 publications

References 37 publications

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Epithelial morphogenesis of MDCK cells in three-dimensional collagen culture is modulated by interleukin-8

Hepatocellular carcinoma a retrospective clinico-pathologic and immunohistochemical study of 15 cases

Contact Info

Product

Resources

About