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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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Taurine inhibits FGF1 release in FGF1/Tek mice and rescues the postischemic kidney recovery.FGF1/Tek mice were fed with water containing taurine (10 mg/ml) or taurine-free water from 2 days before to day 21 after ischemia/reperfusion, when they were sacrificed. FGF1 content in the vasculature was determined by the ELISA method (see Table 1). Four taurine-treated mice with inhibited FGF1 export and six untreated mice were studied. A. Weights of contralateral and postischemic kidneys. Means and SEM are presented. B. Representative hematoxylin/eosin stained paraffin sections of the postischemic and contralateral kidneys of a taurine-treated mouse and a control mouse. Bar −120µ. C. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in taurine-treated and untreated mice. Numbers of epithelial tubular structures in ten ×10 objective fields were counted in postischemic and contralateral kidneys of four FGF1/Tek mice with taurine-inhibited FGF1 release and six FGF1/Tek mice untreated with taurine. D. Paraffin sections of the postischemic and contralateral kidneys of taurine-treated and untreated 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-g006: Taurine inhibits FGF1 release in FGF1/Tek mice and rescues the postischemic kidney recovery.FGF1/Tek mice were fed with water containing taurine (10 mg/ml) or taurine-free water from 2 days before to day 21 after ischemia/reperfusion, when they were sacrificed. FGF1 content in the vasculature was determined by the ELISA method (see Table 1). Four taurine-treated mice with inhibited FGF1 export and six untreated mice were studied. A. Weights of contralateral and postischemic kidneys. Means and SEM are presented. B. Representative hematoxylin/eosin stained paraffin sections of the postischemic and contralateral kidneys of a taurine-treated mouse and a control mouse. Bar −120µ. C. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in taurine-treated and untreated mice. Numbers of epithelial tubular structures in ten ×10 objective fields were counted in postischemic and contralateral kidneys of four FGF1/Tek mice with taurine-inhibited FGF1 release and six FGF1/Tek mice untreated with taurine. D. Paraffin sections of the postischemic and contralateral kidneys of taurine-treated and untreated mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 µ.

Mentions: Besides having significantly increased weight (Figure 6A), postischemic kidneys of mice with FGF1 release repressed by taurine had less interstitial hyperplasia than the postischemic kidneys of animals not treated with taurine (Figure 6B). The postischemic/contralateral ratio of kidney tubule density in mice with repressed FGF1 release (Figure 3C) was almost twice higher than in FGF1/Tek animals untreated with taurine. In addition, unlike taurine untreated animals, mice with FGF1 release repressed with taurine did not exhibit large groups of macrophages and neutrophils in the interstitium of their postischemic kidneys (Figure 3D).


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)

Taurine inhibits FGF1 release in FGF1/Tek mice and rescues the postischemic kidney recovery.FGF1/Tek mice were fed with water containing taurine (10 mg/ml) or taurine-free water from 2 days before to day 21 after ischemia/reperfusion, when they were sacrificed. FGF1 content in the vasculature was determined by the ELISA method (see Table 1). Four taurine-treated mice with inhibited FGF1 export and six untreated mice were studied. A. Weights of contralateral and postischemic kidneys. Means and SEM are presented. B. Representative hematoxylin/eosin stained paraffin sections of the postischemic and contralateral kidneys of a taurine-treated mouse and a control mouse. Bar −120µ. C. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in taurine-treated and untreated mice. Numbers of epithelial tubular structures in ten ×10 objective fields were counted in postischemic and contralateral kidneys of four FGF1/Tek mice with taurine-inhibited FGF1 release and six FGF1/Tek mice untreated with taurine. D. Paraffin sections of the postischemic and contralateral kidneys of taurine-treated and untreated 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-g006: Taurine inhibits FGF1 release in FGF1/Tek mice and rescues the postischemic kidney recovery.FGF1/Tek mice were fed with water containing taurine (10 mg/ml) or taurine-free water from 2 days before to day 21 after ischemia/reperfusion, when they were sacrificed. FGF1 content in the vasculature was determined by the ELISA method (see Table 1). Four taurine-treated mice with inhibited FGF1 export and six untreated mice were studied. A. Weights of contralateral and postischemic kidneys. Means and SEM are presented. B. Representative hematoxylin/eosin stained paraffin sections of the postischemic and contralateral kidneys of a taurine-treated mouse and a control mouse. Bar −120µ. C. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in taurine-treated and untreated mice. Numbers of epithelial tubular structures in ten ×10 objective fields were counted in postischemic and contralateral kidneys of four FGF1/Tek mice with taurine-inhibited FGF1 release and six FGF1/Tek mice untreated with taurine. D. Paraffin sections of the postischemic and contralateral kidneys of taurine-treated and untreated mice were stained using the immunoperoxidase method for a neutrophil marker or F4/80, a macrophage marker. Hematoxylin counterstaining. Bar –40 µ.
Mentions: Besides having significantly increased weight (Figure 6A), postischemic kidneys of mice with FGF1 release repressed by taurine had less interstitial hyperplasia than the postischemic kidneys of animals not treated with taurine (Figure 6B). The postischemic/contralateral ratio of kidney tubule density in mice with repressed FGF1 release (Figure 3C) was almost twice higher than in FGF1/Tek animals untreated with taurine. In addition, unlike taurine untreated animals, mice with FGF1 release repressed with taurine did not exhibit large groups of macrophages and neutrophils in the interstitium of their postischemic kidneys (Figure 3D).

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