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Overexpression of Delayed Rectifier K(+) Channels Promotes In situ Proliferation of Leukocytes in Rat Kidneys with Advanced Chronic Renal Failure.

Kazama I, Maruyama Y, Endo Y, Toyama H, Ejima Y, Matsubara M, Kurosawa S - Int J Nephrol (2012)

Bottom Line: Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF).Age-matched sham-operated rats were used as controls.Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology I, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

ABSTRACT
Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K(+) channels (Kv1.3), and the channels play crucial roles in the activation and proliferation of the cells. Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). In the present study, using a rat model with advanced CRF that underwent 5/6 nephrectomy followed by a 14-week recovery period, we examined the histopathological features of the kidneys and the leukocyte expression of Kv1.3-channels and cell cycle markers. Age-matched sham-operated rats were used as controls. In the cortical interstitium of advanced CRF rat kidneys, leukocytes proliferated in situ and overexpressed Kv1.3 channel protein in their cytoplasm. Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression. This study demonstrated for the first time that the number of leukocytes was dramatically increased in rat kidneys with advanced CRF. The overexpression of Kv1.3 channels in the leukocytes was thought to contribute to the progression of renal fibrosis by stimulating cell cycling and promoting cellular proliferation.

No MeSH data available.


Related in: MedlinePlus

Collagen III and cell cycle marker expression in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (A) Hematoxylin and eosin staining (H&E) in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (a) A low-power view of cortex. Magnification, ×20. (b) A high-power view of cortical interstitium. Magnification, ×60. (B) Immunohistochemistry using antibody for collagen III (brown) in advanced CRF rat kidneys with and without MgTX treatment. (a) and (b) Low-power views of cortex. Magnification, ×20. (C) Cell cycle marker expression. The mRNA abundance of Cdk4 (left) and p21 (right) in the renal cortex of advanced CRF rat kidneys with and without MgTX treatment. *P < 0.05 versus advanced CRF rats without treatment. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.
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fig3: Collagen III and cell cycle marker expression in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (A) Hematoxylin and eosin staining (H&E) in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (a) A low-power view of cortex. Magnification, ×20. (b) A high-power view of cortical interstitium. Magnification, ×60. (B) Immunohistochemistry using antibody for collagen III (brown) in advanced CRF rat kidneys with and without MgTX treatment. (a) and (b) Low-power views of cortex. Magnification, ×20. (C) Cell cycle marker expression. The mRNA abundance of Cdk4 (left) and p21 (right) in the renal cortex of advanced CRF rat kidneys with and without MgTX treatment. *P < 0.05 versus advanced CRF rats without treatment. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.

Mentions: To obtain the direct evidence that the overexpression of Kv1.3 channels actually contributes to the proliferation of leukocytes and to the progression of renal fibrosis, we finally examined CRF rat kidneys after treating with margatoxin, a selective Kv1.3 channel inhibitor [22, 24]. In CRF rat kidneys with margatoxin treatment, proximal tubules were partially preserved, although they were atrophic (Figure 3A(a)). Compared to CRF rat kidneys without treatment (Figures 1A(b) and 1A(d)), the size of the cortical interstitium was smaller (Figure 3A(a)), and the number of infiltrating leukocytes was much less (Figure 3A(b)). Immunohistochemistry for collagen III, a marker of fibrosis, demonstrated less staining in the cortical interstitium of margatoxin-treated CRF rat kidneys (Figure 3B(b) versus 3B(a)), indicating that margatoxin reduced the progression of renal fibrosis. The cortical expression of Cdk4 mRNA was significantly decreased after margatoxin treatment (Figure 3(C), left), and that of p21 mRNA was significantly increased after the treatment (right). These results suggested that the overexpression of Kv1.3 channels in leukocytes was strongly associated with the promotion of cell cycling, and thus with the progression of renal fibrosis.


Overexpression of Delayed Rectifier K(+) Channels Promotes In situ Proliferation of Leukocytes in Rat Kidneys with Advanced Chronic Renal Failure.

Kazama I, Maruyama Y, Endo Y, Toyama H, Ejima Y, Matsubara M, Kurosawa S - Int J Nephrol (2012)

Collagen III and cell cycle marker expression in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (A) Hematoxylin and eosin staining (H&E) in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (a) A low-power view of cortex. Magnification, ×20. (b) A high-power view of cortical interstitium. Magnification, ×60. (B) Immunohistochemistry using antibody for collagen III (brown) in advanced CRF rat kidneys with and without MgTX treatment. (a) and (b) Low-power views of cortex. Magnification, ×20. (C) Cell cycle marker expression. The mRNA abundance of Cdk4 (left) and p21 (right) in the renal cortex of advanced CRF rat kidneys with and without MgTX treatment. *P < 0.05 versus advanced CRF rats without treatment. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369525&req=5

fig3: Collagen III and cell cycle marker expression in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (A) Hematoxylin and eosin staining (H&E) in advanced CRF rat kidneys after margatoxin (MgTX) treatment. (a) A low-power view of cortex. Magnification, ×20. (b) A high-power view of cortical interstitium. Magnification, ×60. (B) Immunohistochemistry using antibody for collagen III (brown) in advanced CRF rat kidneys with and without MgTX treatment. (a) and (b) Low-power views of cortex. Magnification, ×20. (C) Cell cycle marker expression. The mRNA abundance of Cdk4 (left) and p21 (right) in the renal cortex of advanced CRF rat kidneys with and without MgTX treatment. *P < 0.05 versus advanced CRF rats without treatment. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.
Mentions: To obtain the direct evidence that the overexpression of Kv1.3 channels actually contributes to the proliferation of leukocytes and to the progression of renal fibrosis, we finally examined CRF rat kidneys after treating with margatoxin, a selective Kv1.3 channel inhibitor [22, 24]. In CRF rat kidneys with margatoxin treatment, proximal tubules were partially preserved, although they were atrophic (Figure 3A(a)). Compared to CRF rat kidneys without treatment (Figures 1A(b) and 1A(d)), the size of the cortical interstitium was smaller (Figure 3A(a)), and the number of infiltrating leukocytes was much less (Figure 3A(b)). Immunohistochemistry for collagen III, a marker of fibrosis, demonstrated less staining in the cortical interstitium of margatoxin-treated CRF rat kidneys (Figure 3B(b) versus 3B(a)), indicating that margatoxin reduced the progression of renal fibrosis. The cortical expression of Cdk4 mRNA was significantly decreased after margatoxin treatment (Figure 3(C), left), and that of p21 mRNA was significantly increased after the treatment (right). These results suggested that the overexpression of Kv1.3 channels in leukocytes was strongly associated with the promotion of cell cycling, and thus with the progression of renal fibrosis.

Bottom Line: Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF).Age-matched sham-operated rats were used as controls.Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology I, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

ABSTRACT
Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K(+) channels (Kv1.3), and the channels play crucial roles in the activation and proliferation of the cells. Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). In the present study, using a rat model with advanced CRF that underwent 5/6 nephrectomy followed by a 14-week recovery period, we examined the histopathological features of the kidneys and the leukocyte expression of Kv1.3-channels and cell cycle markers. Age-matched sham-operated rats were used as controls. In the cortical interstitium of advanced CRF rat kidneys, leukocytes proliferated in situ and overexpressed Kv1.3 channel protein in their cytoplasm. Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression. This study demonstrated for the first time that the number of leukocytes was dramatically increased in rat kidneys with advanced CRF. The overexpression of Kv1.3 channels in the leukocytes was thought to contribute to the progression of renal fibrosis by stimulating cell cycling and promoting cellular proliferation.

No MeSH data available.


Related in: MedlinePlus