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Transgenic expression of nonclassically secreted FGF suppresses kidney repair.

Kirov A, Duarte M, Guay J, Karolak M, Yan C, Oxburgh L, Prudovsky I - PLoS ONE (2012)

Bottom Line: The effects of nonclassical FGF export in vivo are not sufficiently studied.This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase.We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs.

View Article: PubMed Central - PubMed

Affiliation: Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, United States of America.

ABSTRACT
FGF1 is a signal peptide-less nonclassically released growth factor that is involved in angiogenesis, tissue repair, inflammation, and carcinogenesis. The effects of nonclassical FGF export in vivo are not sufficiently studied. We produced transgenic mice expressing FGF1 in endothelial cells (EC), which allowed the detection of FGF1 export to the vasculature, and studied the efficiency of postischemic kidney repair in these animals. Although FGF1 transgenic mice had a normal phenotype with unperturbed kidney structure, they showed a severely inhibited kidney repair after unilateral ischemia/reperfusion. This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase. In addition, the postischemic kidneys of transgenic mice were characterized by hyperplasia of interstitial cells, paucity of epithelial tubular structures, increase of the areas occupied by connective tissue, and neutrophil and macrophage infiltration. The continuous treatment of transgenic mice with the cell membrane stabilizer, taurine, inhibited nonclassical FGF1 export and significantly rescued postischemic kidney repair. It was also found that similar to EC, the transgenic expression of FGF1 in monocytes and macrophages suppresses kidney repair. We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs.

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Massive infiltration of neutrophils and macrophages in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of the postischemic and contralateral kidneys of FGF1/Tek and control FVB mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 μ.
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pone-0036485-g005: Massive infiltration of neutrophils and macrophages in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of the postischemic and contralateral kidneys of FGF1/Tek and control FVB mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 μ.

Mentions: Kidney fibrosis is enhanced by the invasion of macrophages and neutrophils that serve as sources of various profibrotic growth factors and cytokines [31], [32]. To assess the effect of EC-derived FGF1 on the invasion of inflammatory cells into the kidneys, we used immunoperoxidase histochemistry with the antibody F4/80 (marker of macrophages) or an anti-neutrophil antibody. We found that three weeks after surgery, postischemic FGF1/Tek kidneys contained large groups of macrophages and neutrophils in the interstitium, whereas in the postischemic kidneys of control animals, only individual macrophages and neutrophils were found (Figure 5). Contralateral kidneys of both FGF1/Tek and control animals were also largely macrophage- and neutrophil-negative.


Transgenic expression of nonclassically secreted FGF suppresses kidney repair.

Kirov A, Duarte M, Guay J, Karolak M, Yan C, Oxburgh L, Prudovsky I - PLoS ONE (2012)

Massive infiltration of neutrophils and macrophages in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of the postischemic and contralateral kidneys of FGF1/Tek and control FVB mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 μ.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351418&req=5

pone-0036485-g005: Massive infiltration of neutrophils and macrophages in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of the postischemic and contralateral kidneys of FGF1/Tek and control FVB mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 μ.
Mentions: Kidney fibrosis is enhanced by the invasion of macrophages and neutrophils that serve as sources of various profibrotic growth factors and cytokines [31], [32]. To assess the effect of EC-derived FGF1 on the invasion of inflammatory cells into the kidneys, we used immunoperoxidase histochemistry with the antibody F4/80 (marker of macrophages) or an anti-neutrophil antibody. We found that three weeks after surgery, postischemic FGF1/Tek kidneys contained large groups of macrophages and neutrophils in the interstitium, whereas in the postischemic kidneys of control animals, only individual macrophages and neutrophils were found (Figure 5). Contralateral kidneys of both FGF1/Tek and control animals were also largely macrophage- and neutrophil-negative.

Bottom Line: The effects of nonclassical FGF export in vivo are not sufficiently studied.This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase.We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs.

View Article: PubMed Central - PubMed

Affiliation: Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, United States of America.

ABSTRACT
FGF1 is a signal peptide-less nonclassically released growth factor that is involved in angiogenesis, tissue repair, inflammation, and carcinogenesis. The effects of nonclassical FGF export in vivo are not sufficiently studied. We produced transgenic mice expressing FGF1 in endothelial cells (EC), which allowed the detection of FGF1 export to the vasculature, and studied the efficiency of postischemic kidney repair in these animals. Although FGF1 transgenic mice had a normal phenotype with unperturbed kidney structure, they showed a severely inhibited kidney repair after unilateral ischemia/reperfusion. This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase. In addition, the postischemic kidneys of transgenic mice were characterized by hyperplasia of interstitial cells, paucity of epithelial tubular structures, increase of the areas occupied by connective tissue, and neutrophil and macrophage infiltration. The continuous treatment of transgenic mice with the cell membrane stabilizer, taurine, inhibited nonclassical FGF1 export and significantly rescued postischemic kidney repair. It was also found that similar to EC, the transgenic expression of FGF1 in monocytes and macrophages suppresses kidney repair. We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs.

Show MeSH
Related in: MedlinePlus