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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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Early postischemic response in FGF1/Tek and control animals.A. Expression of the kidney injury marker 1, Havcr1, in the postischemic kidneys of FGF1/Tek and control WT FVB mice one day after ischemia. qRT-PCR results normalized to ß-actin expression. Kidneys of five FGF1/Tek and five WT mice were studied. Mean and SEM are presented. B. PAS staining of the paraffin sections of postischemic and contralateral kidneys of control WT FVB and FGF1/Tek mice. One day after ischemia, hematoxylin counterstaining. Bar –40 μ C. Increase of the percentage of tubules with enlarged lumen (lumen occupies more than ¼ of tubule section) in postischemic kidneys comparatively to contralateral organs. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM of fold increase are presented. D. Glomeruli diameters in postischemic and contralateral kidneys. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM are presented.
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pone-0036485-g002: Early postischemic response in FGF1/Tek and control animals.A. Expression of the kidney injury marker 1, Havcr1, in the postischemic kidneys of FGF1/Tek and control WT FVB mice one day after ischemia. qRT-PCR results normalized to ß-actin expression. Kidneys of five FGF1/Tek and five WT mice were studied. Mean and SEM are presented. B. PAS staining of the paraffin sections of postischemic and contralateral kidneys of control WT FVB and FGF1/Tek mice. One day after ischemia, hematoxylin counterstaining. Bar –40 μ C. Increase of the percentage of tubules with enlarged lumen (lumen occupies more than ¼ of tubule section) in postischemic kidneys comparatively to contralateral organs. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM of fold increase are presented. D. Glomeruli diameters in postischemic and contralateral kidneys. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM are presented.

Mentions: Two- to three-month-old male FGF1/Tek transgenic mice and control male FVB mice were subjected to 26 min of transient ischemia of the right kidney. Day 1 after surgery, the mice were sacrificed and the level of the mouse ortholog of kidney injury marker 1 (KIM1), Havcr1, was determined by qRT-PCR. One day after ischemia, the expression of Havcr1 in FGF1/Tek animals was higher than in control mice (Figure 2A). Despite the trend of increased Havcr1 expression in transgenic mice relative to WT, differences between the two genotypes did not reach p<0.05. PAS staining of kidney sections demonstrated that 24 h after ischemia, the postischemic kidneys of both FGF1/Tek and control animals contained in contrast to contralateral organs epithelial tubules, filled with PAS-positive protein casts characteristic of acute kidney injury (Figure 2B). Postischemic kidneys were characterized by an increase of the percentage of dilated tubules, and this increase was not significantly different between FGF1/Tek and control animals (Figure 2C). Ischemia did not result in a significant change of the diameters of glomeruli in the kidneys of both FGF1/Tek and control mice (Figure 2D).


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)

Early postischemic response in FGF1/Tek and control animals.A. Expression of the kidney injury marker 1, Havcr1, in the postischemic kidneys of FGF1/Tek and control WT FVB mice one day after ischemia. qRT-PCR results normalized to ß-actin expression. Kidneys of five FGF1/Tek and five WT mice were studied. Mean and SEM are presented. B. PAS staining of the paraffin sections of postischemic and contralateral kidneys of control WT FVB and FGF1/Tek mice. One day after ischemia, hematoxylin counterstaining. Bar –40 μ C. Increase of the percentage of tubules with enlarged lumen (lumen occupies more than ¼ of tubule section) in postischemic kidneys comparatively to contralateral organs. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM of fold increase are presented. D. Glomeruli diameters in postischemic and contralateral kidneys. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM are presented.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036485-g002: Early postischemic response in FGF1/Tek and control animals.A. Expression of the kidney injury marker 1, Havcr1, in the postischemic kidneys of FGF1/Tek and control WT FVB mice one day after ischemia. qRT-PCR results normalized to ß-actin expression. Kidneys of five FGF1/Tek and five WT mice were studied. Mean and SEM are presented. B. PAS staining of the paraffin sections of postischemic and contralateral kidneys of control WT FVB and FGF1/Tek mice. One day after ischemia, hematoxylin counterstaining. Bar –40 μ C. Increase of the percentage of tubules with enlarged lumen (lumen occupies more than ¼ of tubule section) in postischemic kidneys comparatively to contralateral organs. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM of fold increase are presented. D. Glomeruli diameters in postischemic and contralateral kidneys. Kidneys of four FGF1/Tek and four WT mice were studied. Mean and SEM are presented.
Mentions: Two- to three-month-old male FGF1/Tek transgenic mice and control male FVB mice were subjected to 26 min of transient ischemia of the right kidney. Day 1 after surgery, the mice were sacrificed and the level of the mouse ortholog of kidney injury marker 1 (KIM1), Havcr1, was determined by qRT-PCR. One day after ischemia, the expression of Havcr1 in FGF1/Tek animals was higher than in control mice (Figure 2A). Despite the trend of increased Havcr1 expression in transgenic mice relative to WT, differences between the two genotypes did not reach p<0.05. PAS staining of kidney sections demonstrated that 24 h after ischemia, the postischemic kidneys of both FGF1/Tek and control animals contained in contrast to contralateral organs epithelial tubules, filled with PAS-positive protein casts characteristic of acute kidney injury (Figure 2B). Postischemic kidneys were characterized by an increase of the percentage of dilated tubules, and this increase was not significantly different between FGF1/Tek and control animals (Figure 2C). Ischemia did not result in a significant change of the diameters of glomeruli in the kidneys of both FGF1/Tek and control mice (Figure 2D).

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