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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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Histological analysis of CXCR7-deficient kidneys.Kidney sections of E16.5 wildtype (A–C) and CXCR7 deficient littermates (D–F) were stained with periodic acid-Schiff (PAS) reagents. (A,D) Macroscopic images demonstrate that the overall kidney morphology is normal in the CXCR7 knockout embryo. (B,C,E,F) Microscopic views of pretubular aggregates (pa), renal vesicles (rv), ureteric buds (ub) (B,E), and S-shaped bodies (C,F) do not reveal any abnormalities in the CXCR7 knockout kidney. Scale bars equal 200 µm (D) and 20 µm (B,C).
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pone-0042814-g004: Histological analysis of CXCR7-deficient kidneys.Kidney sections of E16.5 wildtype (A–C) and CXCR7 deficient littermates (D–F) were stained with periodic acid-Schiff (PAS) reagents. (A,D) Macroscopic images demonstrate that the overall kidney morphology is normal in the CXCR7 knockout embryo. (B,C,E,F) Microscopic views of pretubular aggregates (pa), renal vesicles (rv), ureteric buds (ub) (B,E), and S-shaped bodies (C,F) do not reveal any abnormalities in the CXCR7 knockout kidney. Scale bars equal 200 µm (D) and 20 µm (B,C).

Mentions: Given the strong expression of the CXCR7 gene in the developing kidney, we were then interested if kidney development was affected in CXCR7−/− mice. To this end, we first analyzed counterstained serial sections from E14.5 and E16.5 CXCR7−/− mice as well as CXCR7+/− and CXCR7+/+ control littermates. Using this approach, we failed to identify any severe defects in kidney morphology and nephrogenesis (Figure 4). Both cohorts developed similar sized kidneys (E14.5: CXCR7−/−, 0.151±0.016 mm3; Control, 0.175±0.018 mm3) and the same number of glomeruli (E14.5: CXCR7−/−, 57.0±8.84; Control, 55.4±14.2). Within the glomeruli, urinary space tended to be enlarged in the CXCR7 mutants (E14.5: CXCR7−/−, 710.2±124.3 µm2; Control, 514.7±42.3 µm2).


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)

Histological analysis of CXCR7-deficient kidneys.Kidney sections of E16.5 wildtype (A–C) and CXCR7 deficient littermates (D–F) were stained with periodic acid-Schiff (PAS) reagents. (A,D) Macroscopic images demonstrate that the overall kidney morphology is normal in the CXCR7 knockout embryo. (B,C,E,F) Microscopic views of pretubular aggregates (pa), renal vesicles (rv), ureteric buds (ub) (B,E), and S-shaped bodies (C,F) do not reveal any abnormalities in the CXCR7 knockout kidney. Scale bars equal 200 µm (D) and 20 µm (B,C).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412803&req=5

pone-0042814-g004: Histological analysis of CXCR7-deficient kidneys.Kidney sections of E16.5 wildtype (A–C) and CXCR7 deficient littermates (D–F) were stained with periodic acid-Schiff (PAS) reagents. (A,D) Macroscopic images demonstrate that the overall kidney morphology is normal in the CXCR7 knockout embryo. (B,C,E,F) Microscopic views of pretubular aggregates (pa), renal vesicles (rv), ureteric buds (ub) (B,E), and S-shaped bodies (C,F) do not reveal any abnormalities in the CXCR7 knockout kidney. Scale bars equal 200 µm (D) and 20 µm (B,C).
Mentions: Given the strong expression of the CXCR7 gene in the developing kidney, we were then interested if kidney development was affected in CXCR7−/− mice. To this end, we first analyzed counterstained serial sections from E14.5 and E16.5 CXCR7−/− mice as well as CXCR7+/− and CXCR7+/+ control littermates. Using this approach, we failed to identify any severe defects in kidney morphology and nephrogenesis (Figure 4). Both cohorts developed similar sized kidneys (E14.5: CXCR7−/−, 0.151±0.016 mm3; Control, 0.175±0.018 mm3) and the same number of glomeruli (E14.5: CXCR7−/−, 57.0±8.84; Control, 55.4±14.2). Within the glomeruli, urinary space tended to be enlarged in the CXCR7 mutants (E14.5: CXCR7−/−, 710.2±124.3 µm2; Control, 514.7±42.3 µm2).

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