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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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Decrease of postischemic kidney size and loss of tubular epithelial structures in FGF1/Tek animals.A. Representative contralateral and postischemic kidneys of FGF1/Tek and control FVB (WT) animals, 21 days after ischemia/reperfusion. B. Decrease of postischemic kidneys weight (red) and increase of contralateral kidneys weight (blue) in FGF1/Tek mice compared to FVB mice (WT). Mean and SEM are presented. C. Sections of contralateral (two top sections per slide) and postischemic (two bottom sections per slide) kidneys of FGF1/Tek and control mice. D. Loss of tubular structures in a postischemic kidney of an FGF1/Tek mouse. Postischemic and contralateral kidneys of an FGF1/Tek and a control WT mouse are presented. Hematoxylin/eosin stained paraffin sections. Bar −120µ. E. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in FGF1/Tek and WT mice. Numbers of epithelial tubular structures in ten ×10 objective field were counted in postischemic and contralateral kidneys of four FGF1/Tek and four wild type mice.
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pone-0036485-g003: Decrease of postischemic kidney size and loss of tubular epithelial structures in FGF1/Tek animals.A. Representative contralateral and postischemic kidneys of FGF1/Tek and control FVB (WT) animals, 21 days after ischemia/reperfusion. B. Decrease of postischemic kidneys weight (red) and increase of contralateral kidneys weight (blue) in FGF1/Tek mice compared to FVB mice (WT). Mean and SEM are presented. C. Sections of contralateral (two top sections per slide) and postischemic (two bottom sections per slide) kidneys of FGF1/Tek and control mice. D. Loss of tubular structures in a postischemic kidney of an FGF1/Tek mouse. Postischemic and contralateral kidneys of an FGF1/Tek and a control WT mouse are presented. Hematoxylin/eosin stained paraffin sections. Bar −120µ. E. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in FGF1/Tek and WT mice. Numbers of epithelial tubular structures in ten ×10 objective field were counted in postischemic and contralateral kidneys of four FGF1/Tek and four wild type mice.

Mentions: Three weeks after unilateral ischemia/reperfusion, postischemic kidneys of FGF1/Tek animals presented a sharp morphological contrast to control animals. Indeed, their weight was on average 25% less than in the control mice (Figure 3A,B,C). Hematoxylin-eosin staining of paraffin sections revealed a failure of kidney repair in postischemic FGF1/Tek animals. Indeed, three weeks after surgery, the postischemic kidneys of FGF1/Tek mice exhibited a paucity of epithelial tubules, combined with hyperplasia of interstitial cells (Figure 3D,E). Conversely, the histology of postischemic kidneys in control WT animals was more similar to that of contralateral organs: efficient restoration of tubular structures, and few signs of interstitial hyperplasia. The ratio of tubule density in postischemic FGF1/Tek mice kidneys to tubule density in contralateral kidneys (Figure 3E) was sharply lower than this parameter in WT mice. The postischemic kidneys of FGF1/Tek animals contained abundant capillaries detected by anti-PECAM staining (Figure S1). Thus, it is unlikely that the observed changes were due to deficient angiogenesis.


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)

Decrease of postischemic kidney size and loss of tubular epithelial structures in FGF1/Tek animals.A. Representative contralateral and postischemic kidneys of FGF1/Tek and control FVB (WT) animals, 21 days after ischemia/reperfusion. B. Decrease of postischemic kidneys weight (red) and increase of contralateral kidneys weight (blue) in FGF1/Tek mice compared to FVB mice (WT). Mean and SEM are presented. C. Sections of contralateral (two top sections per slide) and postischemic (two bottom sections per slide) kidneys of FGF1/Tek and control mice. D. Loss of tubular structures in a postischemic kidney of an FGF1/Tek mouse. Postischemic and contralateral kidneys of an FGF1/Tek and a control WT mouse are presented. Hematoxylin/eosin stained paraffin sections. Bar −120µ. E. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in FGF1/Tek and WT mice. Numbers of epithelial tubular structures in ten ×10 objective field were counted in postischemic and contralateral kidneys of four FGF1/Tek and four wild type mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036485-g003: Decrease of postischemic kidney size and loss of tubular epithelial structures in FGF1/Tek animals.A. Representative contralateral and postischemic kidneys of FGF1/Tek and control FVB (WT) animals, 21 days after ischemia/reperfusion. B. Decrease of postischemic kidneys weight (red) and increase of contralateral kidneys weight (blue) in FGF1/Tek mice compared to FVB mice (WT). Mean and SEM are presented. C. Sections of contralateral (two top sections per slide) and postischemic (two bottom sections per slide) kidneys of FGF1/Tek and control mice. D. Loss of tubular structures in a postischemic kidney of an FGF1/Tek mouse. Postischemic and contralateral kidneys of an FGF1/Tek and a control WT mouse are presented. Hematoxylin/eosin stained paraffin sections. Bar −120µ. E. Postischemic/contralateral % ratio (mean and SEM) of kidney tubule density in FGF1/Tek and WT mice. Numbers of epithelial tubular structures in ten ×10 objective field were counted in postischemic and contralateral kidneys of four FGF1/Tek and four wild type mice.
Mentions: Three weeks after unilateral ischemia/reperfusion, postischemic kidneys of FGF1/Tek animals presented a sharp morphological contrast to control animals. Indeed, their weight was on average 25% less than in the control mice (Figure 3A,B,C). Hematoxylin-eosin staining of paraffin sections revealed a failure of kidney repair in postischemic FGF1/Tek animals. Indeed, three weeks after surgery, the postischemic kidneys of FGF1/Tek mice exhibited a paucity of epithelial tubules, combined with hyperplasia of interstitial cells (Figure 3D,E). Conversely, the histology of postischemic kidneys in control WT animals was more similar to that of contralateral organs: efficient restoration of tubular structures, and few signs of interstitial hyperplasia. The ratio of tubule density in postischemic FGF1/Tek mice kidneys to tubule density in contralateral kidneys (Figure 3E) was sharply lower than this parameter in WT mice. The postischemic kidneys of FGF1/Tek animals contained abundant capillaries detected by anti-PECAM staining (Figure S1). Thus, it is unlikely that the observed changes were due to deficient angiogenesis.

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