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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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Fibrosis and cell proliferation in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of postischemic and contralateral kidneys of FGF1/Tek and control FVB mice. A. Trichrome staining. B. Sirius red staining for collagen. Polarization microscopy. C. Immunoperoxidase staining for Ki-67, a marker of cell proliferation. In B and C, hematoxylin counterstaining was used. Bar in A –80 µ. Bars in B and C –40 µ. D. Quantification of Sirius staining: % of kidney section area positive for Sirius Red (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied. E. Quantification of cell proliferation: % cells positive for Ki-67 (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied.
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pone-0036485-g004: Fibrosis and cell proliferation in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of postischemic and contralateral kidneys of FGF1/Tek and control FVB mice. A. Trichrome staining. B. Sirius red staining for collagen. Polarization microscopy. C. Immunoperoxidase staining for Ki-67, a marker of cell proliferation. In B and C, hematoxylin counterstaining was used. Bar in A –80 µ. Bars in B and C –40 µ. D. Quantification of Sirius staining: % of kidney section area positive for Sirius Red (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied. E. Quantification of cell proliferation: % cells positive for Ki-67 (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied.

Mentions: Abundance of interstitial cells in postischemic kidneys of FGF1/Tek mice prompted us to assess fibrosis and cell proliferation in these organs. Trichrome staining (Figure 4A) revealed a strong expansion of connective tissue in the cortex and medulla of postischemic kidneys of FGF1/Tek mice compared to control animals. Staining with the collagen marker Sirius Red was increased in the interstitium of postischemic FGF1/Tek kidneys much stronger than in postischemic kidneys of control mice (Figure 4B, D). Immunohistochemical staining for Ki-67 a marker of cell proliferation, revealed numerous proliferating cells in the hyperplastic interstitium of cortex and medulla of FGF1/Tek kidneys, while Ki-67-positive cells were rare in postischemic kidneys of control animals (4C, E).


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)

Fibrosis and cell proliferation in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of postischemic and contralateral kidneys of FGF1/Tek and control FVB mice. A. Trichrome staining. B. Sirius red staining for collagen. Polarization microscopy. C. Immunoperoxidase staining for Ki-67, a marker of cell proliferation. In B and C, hematoxylin counterstaining was used. Bar in A –80 µ. Bars in B and C –40 µ. D. Quantification of Sirius staining: % of kidney section area positive for Sirius Red (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied. E. Quantification of cell proliferation: % cells positive for Ki-67 (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351418&req=5

pone-0036485-g004: Fibrosis and cell proliferation in the postischemic kidneys of FGF1/Tek mice.Twenty-one days after ischemia, paraffin sections of postischemic and contralateral kidneys of FGF1/Tek and control FVB mice. A. Trichrome staining. B. Sirius red staining for collagen. Polarization microscopy. C. Immunoperoxidase staining for Ki-67, a marker of cell proliferation. In B and C, hematoxylin counterstaining was used. Bar in A –80 µ. Bars in B and C –40 µ. D. Quantification of Sirius staining: % of kidney section area positive for Sirius Red (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied. E. Quantification of cell proliferation: % cells positive for Ki-67 (mean and SEM) is presented. Kidneys of four FGF1/Tek and four WT mice were studied.
Mentions: Abundance of interstitial cells in postischemic kidneys of FGF1/Tek mice prompted us to assess fibrosis and cell proliferation in these organs. Trichrome staining (Figure 4A) revealed a strong expansion of connective tissue in the cortex and medulla of postischemic kidneys of FGF1/Tek mice compared to control animals. Staining with the collagen marker Sirius Red was increased in the interstitium of postischemic FGF1/Tek kidneys much stronger than in postischemic kidneys of control mice (Figure 4B, D). Immunohistochemical staining for Ki-67 a marker of cell proliferation, revealed numerous proliferating cells in the hyperplastic interstitium of cortex and medulla of FGF1/Tek kidneys, while Ki-67-positive cells were rare in postischemic kidneys of control animals (4C, E).

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