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CXC chemokine receptor 7 (CXCR7) regulates CXCR4 protein expression and capillary tuft development in mouse kidney.

Haege S, Einer C, Thiele S, Mueller W, Nietzsche S, Lupp A, Mackay F, Schulz S, Stumm R - PLoS ONE (2012)

Bottom Line: Moreover, we detected a severe reduction of CXCR4 protein but not CXCR4 mRNA within the glomerular tuft and in the condensed mesenchyme.We established that there is a similar glomerular pathology in CXCR7 and CXCR4 embryos.Based on the phenotype and the anatomical organization of the CXCL12/CXCR4/CXCR7 system in the forming glomerulus, we propose that CXCR7 fine-tunes CXCL12/CXCR4 mediated signalling between podocytes and glomerular capillaries.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany. sammy.haege@mti.uni-jena.de

ABSTRACT

Background: The CXCL12/CXCR4 axis is involved in kidney development by regulating formation of the glomerular tuft. Recently, a second CXCL12 receptor was identified and designated CXCR7. Although it is established that CXCR7 regulates heart and brain development in conjunction with CXCL12 and CXCR4, little is known about the influence of CXCR7 on CXCL12 dependent kidney development.

Methodology/principal findings: We provided analysis of CXCR7 expression and function in the developing mouse kidney. Using in situ hybridization, we identified CXCR7 mRNA in epithelial cells including podocytes at all nephron stages up to the mature glomerulus. CXCL12 mRNA showed a striking overlap with CXCR7 mRNA in epithelial structures. In addition, CXCL12 was detected in stromal cells and the glomerular tuft. Expression of CXCR4 was complementary to that of CXCR7 as it occurred in mesenchymal cells, outgrowing ureteric buds and glomerular endothelial cells but not in podocytes. Kidney examination in CXCR7 mice revealed ballooning of glomerular capillaries as described earlier for CXCR4 mice. Moreover, we detected a severe reduction of CXCR4 protein but not CXCR4 mRNA within the glomerular tuft and in the condensed mesenchyme. Malformation of the glomerular tuft in CXCR7 mice was associated with mesangial cell clumping.

Conclusions/significance: We established that there is a similar glomerular pathology in CXCR7 and CXCR4 embryos. Based on the phenotype and the anatomical organization of the CXCL12/CXCR4/CXCR7 system in the forming glomerulus, we propose that CXCR7 fine-tunes CXCL12/CXCR4 mediated signalling between podocytes and glomerular capillaries.

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Patterns of CXCL12, CXCR7, and CXCR4 mRNAs in the early developing kidney.Adjacent kidney sections were hybridized with radiolabeled antisense riboprobes for CXCL12, CXCR7, and CXCR4 at E12.5 and E14.5. (A, D) CXCL12 expression pattern changed remarkably from E12.5 to E14.5 as no CXCL12 mRNA could be detected within the E12.5 kidney. At E14.5, CXCL12 signals are present in the kidney in stromal cells (asteristics in D), around the ureter (u) as well as in glomeruli (arrowheads in D). (B, E) CXCR7 mRNA is expressed in the region of the renal capsule (rc) and ureter at both indicated embryonic stages. The gene is also active in some ureteric buds (open arrows in B, E), immature glomeruli (closed arrows in E), and mature glomeruli (arrowheads in E). (C, F) CXCR4 mRNA is highly expressed in mesenchymal cells below the rc region at E12.5 (arrowheads in C) as well as in the cap mesenchyme at E14.5 (cm in F). CXCR4 is also expressed in some ureteric buds at E12.5 (open arrows in C). At E14.5, CXCR4 expression is found in presumptive blood vessels (closed arrows in F) and glomerular tufts (arrowheads in F). Allocation of detection signals to renal structures was performed using counterstaining with hematoxylin & eosin. ag, adrenal gland; ov, ovarium; Scale bars correspond to 100 µm.
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pone-0042814-g001: Patterns of CXCL12, CXCR7, and CXCR4 mRNAs in the early developing kidney.Adjacent kidney sections were hybridized with radiolabeled antisense riboprobes for CXCL12, CXCR7, and CXCR4 at E12.5 and E14.5. (A, D) CXCL12 expression pattern changed remarkably from E12.5 to E14.5 as no CXCL12 mRNA could be detected within the E12.5 kidney. At E14.5, CXCL12 signals are present in the kidney in stromal cells (asteristics in D), around the ureter (u) as well as in glomeruli (arrowheads in D). (B, E) CXCR7 mRNA is expressed in the region of the renal capsule (rc) and ureter at both indicated embryonic stages. The gene is also active in some ureteric buds (open arrows in B, E), immature glomeruli (closed arrows in E), and mature glomeruli (arrowheads in E). (C, F) CXCR4 mRNA is highly expressed in mesenchymal cells below the rc region at E12.5 (arrowheads in C) as well as in the cap mesenchyme at E14.5 (cm in F). CXCR4 is also expressed in some ureteric buds at E12.5 (open arrows in C). At E14.5, CXCR4 expression is found in presumptive blood vessels (closed arrows in F) and glomerular tufts (arrowheads in F). Allocation of detection signals to renal structures was performed using counterstaining with hematoxylin & eosin. ag, adrenal gland; ov, ovarium; Scale bars correspond to 100 µm.

Mentions: We first investigated mRNA expression of CXCR7 to match these data with CXCL12 and CXCR4 expression patterns at embryonic stages E12.5 and E14.5 using radiolabeled in situ hybridization (Figure 1). At E12.5, CXCL12 mRNA was transiently expressed in the mesenchyme outside the developing kidney near the region of the renal capsule (Figure 1A) whereas CXCR7 was expressed predominantly in the renal mesenchyme near the forming capsule (Figure 1B: rc). This CXCR7 expression at the capsule was also detected at E14.5 (Figure 1E: rc) and persisted up to perinatal kidney (data not shown). The CXCR4 gene however was strongly expressed in more deeper layered mesenchymal cells (Figure 1C: arrowheads), which are in close proximity to outgrowing ureteric buds (UB). Some of these ureteric buds were CXCR7 and CXCR4 positive at E12.5 and E14.5 (Figure 1B,C,E: open arrows), whereas all UB tips were negative for both genes at later developmental stages (data not shown). In contrast to CXCR7 and CXCL12, CXCR4 transcripts were strongly expressed in the condensed mesenchyme at E14.5 (Figure 1F: cm) up to birth (data not shown). At this embryonic stage, CXCL12 expression was turned on in stromal cells (Figure 1D: asteristics), which derive from CXCL12 negative cells of the loose mesenchyme.


CXC chemokine receptor 7 (CXCR7) regulates CXCR4 protein expression and capillary tuft development in mouse kidney.

Haege S, Einer C, Thiele S, Mueller W, Nietzsche S, Lupp A, Mackay F, Schulz S, Stumm R - PLoS ONE (2012)

Patterns of CXCL12, CXCR7, and CXCR4 mRNAs in the early developing kidney.Adjacent kidney sections were hybridized with radiolabeled antisense riboprobes for CXCL12, CXCR7, and CXCR4 at E12.5 and E14.5. (A, D) CXCL12 expression pattern changed remarkably from E12.5 to E14.5 as no CXCL12 mRNA could be detected within the E12.5 kidney. At E14.5, CXCL12 signals are present in the kidney in stromal cells (asteristics in D), around the ureter (u) as well as in glomeruli (arrowheads in D). (B, E) CXCR7 mRNA is expressed in the region of the renal capsule (rc) and ureter at both indicated embryonic stages. The gene is also active in some ureteric buds (open arrows in B, E), immature glomeruli (closed arrows in E), and mature glomeruli (arrowheads in E). (C, F) CXCR4 mRNA is highly expressed in mesenchymal cells below the rc region at E12.5 (arrowheads in C) as well as in the cap mesenchyme at E14.5 (cm in F). CXCR4 is also expressed in some ureteric buds at E12.5 (open arrows in C). At E14.5, CXCR4 expression is found in presumptive blood vessels (closed arrows in F) and glomerular tufts (arrowheads in F). Allocation of detection signals to renal structures was performed using counterstaining with hematoxylin & eosin. ag, adrenal gland; ov, ovarium; Scale bars correspond to 100 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412803&req=5

pone-0042814-g001: Patterns of CXCL12, CXCR7, and CXCR4 mRNAs in the early developing kidney.Adjacent kidney sections were hybridized with radiolabeled antisense riboprobes for CXCL12, CXCR7, and CXCR4 at E12.5 and E14.5. (A, D) CXCL12 expression pattern changed remarkably from E12.5 to E14.5 as no CXCL12 mRNA could be detected within the E12.5 kidney. At E14.5, CXCL12 signals are present in the kidney in stromal cells (asteristics in D), around the ureter (u) as well as in glomeruli (arrowheads in D). (B, E) CXCR7 mRNA is expressed in the region of the renal capsule (rc) and ureter at both indicated embryonic stages. The gene is also active in some ureteric buds (open arrows in B, E), immature glomeruli (closed arrows in E), and mature glomeruli (arrowheads in E). (C, F) CXCR4 mRNA is highly expressed in mesenchymal cells below the rc region at E12.5 (arrowheads in C) as well as in the cap mesenchyme at E14.5 (cm in F). CXCR4 is also expressed in some ureteric buds at E12.5 (open arrows in C). At E14.5, CXCR4 expression is found in presumptive blood vessels (closed arrows in F) and glomerular tufts (arrowheads in F). Allocation of detection signals to renal structures was performed using counterstaining with hematoxylin & eosin. ag, adrenal gland; ov, ovarium; Scale bars correspond to 100 µm.
Mentions: We first investigated mRNA expression of CXCR7 to match these data with CXCL12 and CXCR4 expression patterns at embryonic stages E12.5 and E14.5 using radiolabeled in situ hybridization (Figure 1). At E12.5, CXCL12 mRNA was transiently expressed in the mesenchyme outside the developing kidney near the region of the renal capsule (Figure 1A) whereas CXCR7 was expressed predominantly in the renal mesenchyme near the forming capsule (Figure 1B: rc). This CXCR7 expression at the capsule was also detected at E14.5 (Figure 1E: rc) and persisted up to perinatal kidney (data not shown). The CXCR4 gene however was strongly expressed in more deeper layered mesenchymal cells (Figure 1C: arrowheads), which are in close proximity to outgrowing ureteric buds (UB). Some of these ureteric buds were CXCR7 and CXCR4 positive at E12.5 and E14.5 (Figure 1B,C,E: open arrows), whereas all UB tips were negative for both genes at later developmental stages (data not shown). In contrast to CXCR7 and CXCL12, CXCR4 transcripts were strongly expressed in the condensed mesenchyme at E14.5 (Figure 1F: cm) up to birth (data not shown). At this embryonic stage, CXCL12 expression was turned on in stromal cells (Figure 1D: asteristics), which derive from CXCL12 negative cells of the loose mesenchyme.

Bottom Line: Moreover, we detected a severe reduction of CXCR4 protein but not CXCR4 mRNA within the glomerular tuft and in the condensed mesenchyme.We established that there is a similar glomerular pathology in CXCR7 and CXCR4 embryos.Based on the phenotype and the anatomical organization of the CXCL12/CXCR4/CXCR7 system in the forming glomerulus, we propose that CXCR7 fine-tunes CXCL12/CXCR4 mediated signalling between podocytes and glomerular capillaries.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany. sammy.haege@mti.uni-jena.de

ABSTRACT

Background: The CXCL12/CXCR4 axis is involved in kidney development by regulating formation of the glomerular tuft. Recently, a second CXCL12 receptor was identified and designated CXCR7. Although it is established that CXCR7 regulates heart and brain development in conjunction with CXCL12 and CXCR4, little is known about the influence of CXCR7 on CXCL12 dependent kidney development.

Methodology/principal findings: We provided analysis of CXCR7 expression and function in the developing mouse kidney. Using in situ hybridization, we identified CXCR7 mRNA in epithelial cells including podocytes at all nephron stages up to the mature glomerulus. CXCL12 mRNA showed a striking overlap with CXCR7 mRNA in epithelial structures. In addition, CXCL12 was detected in stromal cells and the glomerular tuft. Expression of CXCR4 was complementary to that of CXCR7 as it occurred in mesenchymal cells, outgrowing ureteric buds and glomerular endothelial cells but not in podocytes. Kidney examination in CXCR7 mice revealed ballooning of glomerular capillaries as described earlier for CXCR4 mice. Moreover, we detected a severe reduction of CXCR4 protein but not CXCR4 mRNA within the glomerular tuft and in the condensed mesenchyme. Malformation of the glomerular tuft in CXCR7 mice was associated with mesangial cell clumping.

Conclusions/significance: We established that there is a similar glomerular pathology in CXCR7 and CXCR4 embryos. Based on the phenotype and the anatomical organization of the CXCL12/CXCR4/CXCR7 system in the forming glomerulus, we propose that CXCR7 fine-tunes CXCL12/CXCR4 mediated signalling between podocytes and glomerular capillaries.

Show MeSH
Related in: MedlinePlus