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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

Kv1.3 and cell cycle marker expression in sham operated (sham) and advanced CRF rat kidneys. (A) Kv1.3 expression. (a) KCNA3 mRNA abundance in the renal cortex of sham operated (sham) and advanced CRF (CRF) rat kidneys. (b) and (c) Immunohistochemistry using antibody for Kv1.3 (brown) in sham operated and advanced CRF rat kidneys. High-power views of cortical interstitium. Magnification, ×60. (B) Cell cycle marker expression. The mRNA abundance of cyclin-dependent kinase 4 (Cdk4) (left) and p21 (right) in the renal cortex of sham operated and advanced CRF rat kidneys. #P < 0.05 versus sham operated rats. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.
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fig2: Kv1.3 and cell cycle marker expression in sham operated (sham) and advanced CRF rat kidneys. (A) Kv1.3 expression. (a) KCNA3 mRNA abundance in the renal cortex of sham operated (sham) and advanced CRF (CRF) rat kidneys. (b) and (c) Immunohistochemistry using antibody for Kv1.3 (brown) in sham operated and advanced CRF rat kidneys. High-power views of cortical interstitium. Magnification, ×60. (B) Cell cycle marker expression. The mRNA abundance of cyclin-dependent kinase 4 (Cdk4) (left) and p21 (right) in the renal cortex of sham operated and advanced CRF rat kidneys. #P < 0.05 versus sham operated rats. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.

Mentions: Since lymphocytes and macrophages express Kv1.3 channels in their plasma membranes [13, 14], and since the channels trigger the calcium influx necessary for cellular proliferation [15, 16], we examined the expression of the channel in leukocytes of the rat kidneys (Figure 2(A)). The mRNA expression of KCNA3 gene, which encodes Kv1.3, was markedly elevated in the cortex isolated from CRF rat kidneys (Figure 2A(a)). In sham operated rats, as previously demonstrated [21], immunohistochemistry for Kv1.3 showed a weak staining in the cytoplasm of some proximal tubular cells (Figure 2A(b), arrows), but not in small round cells in the cortical interstitium (arrow heads). In CRF rats, however, the cytoplasmic expression of Kv1.3 was increased specifically in small round cells proliferating in the cortical interstitium (Figure 2A(c), arrow heads), indicating the overexpression of the channels in the leukocytes.


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)

Kv1.3 and cell cycle marker expression in sham operated (sham) and advanced CRF rat kidneys. (A) Kv1.3 expression. (a) KCNA3 mRNA abundance in the renal cortex of sham operated (sham) and advanced CRF (CRF) rat kidneys. (b) and (c) Immunohistochemistry using antibody for Kv1.3 (brown) in sham operated and advanced CRF rat kidneys. High-power views of cortical interstitium. Magnification, ×60. (B) Cell cycle marker expression. The mRNA abundance of cyclin-dependent kinase 4 (Cdk4) (left) and p21 (right) in the renal cortex of sham operated and advanced CRF rat kidneys. #P < 0.05 versus sham operated rats. 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

Show All Figures
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fig2: Kv1.3 and cell cycle marker expression in sham operated (sham) and advanced CRF rat kidneys. (A) Kv1.3 expression. (a) KCNA3 mRNA abundance in the renal cortex of sham operated (sham) and advanced CRF (CRF) rat kidneys. (b) and (c) Immunohistochemistry using antibody for Kv1.3 (brown) in sham operated and advanced CRF rat kidneys. High-power views of cortical interstitium. Magnification, ×60. (B) Cell cycle marker expression. The mRNA abundance of cyclin-dependent kinase 4 (Cdk4) (left) and p21 (right) in the renal cortex of sham operated and advanced CRF rat kidneys. #P < 0.05 versus sham operated rats. Values are means ± SEM (n = 6). Differences were analyzed by ANOVA followed by Dunnett's or Student's t-test.
Mentions: Since lymphocytes and macrophages express Kv1.3 channels in their plasma membranes [13, 14], and since the channels trigger the calcium influx necessary for cellular proliferation [15, 16], we examined the expression of the channel in leukocytes of the rat kidneys (Figure 2(A)). The mRNA expression of KCNA3 gene, which encodes Kv1.3, was markedly elevated in the cortex isolated from CRF rat kidneys (Figure 2A(a)). In sham operated rats, as previously demonstrated [21], immunohistochemistry for Kv1.3 showed a weak staining in the cytoplasm of some proximal tubular cells (Figure 2A(b), arrows), but not in small round cells in the cortical interstitium (arrow heads). In CRF rats, however, the cytoplasmic expression of Kv1.3 was increased specifically in small round cells proliferating in the cortical interstitium (Figure 2A(c), arrow heads), indicating the overexpression of the channels in the leukocytes.

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