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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

Histological features of sham operated (sham) and advanced CRF rat kidneys. (A) Hematoxylin and eosin staining (H&E) in sham operated (sham) and advanced CRF rat kidneys. (a) and (b) Low-power views of cortex. Magnification, ×20. (c) and (d) High-power views of cortical interstitium. Magnification, ×60. (B) The mRNA abundance of CD3 (left) and ED-1 (right) in the renal cortex of sham operated and advanced CRF (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. (C) Immunohistochemistry using antibody for Ki-67 (brown) in sham operated and advanced CRF rat kidneys. (a) and (b) High-power views of cortical interstitium. Magnification, ×60.
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fig1: Histological features of sham operated (sham) and advanced CRF rat kidneys. (A) Hematoxylin and eosin staining (H&E) in sham operated (sham) and advanced CRF rat kidneys. (a) and (b) Low-power views of cortex. Magnification, ×20. (c) and (d) High-power views of cortical interstitium. Magnification, ×60. (B) The mRNA abundance of CD3 (left) and ED-1 (right) in the renal cortex of sham operated and advanced CRF (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. (C) Immunohistochemistry using antibody for Ki-67 (brown) in sham operated and advanced CRF rat kidneys. (a) and (b) High-power views of cortical interstitium. Magnification, ×60.

Mentions: The marked elevation of serum creatinine (4.45 ± 1.16 versus sham operated 0.33 ± 0.03 mg/dL, n = 6, P < 0.05) and urea nitrogen (130 ± 8.95 versus sham operated 15.5 ± 1.39 mg/dL, n = 6, P < 0.05) levels in nephrectomized rats indicated advanced CRF with severe uremia [11]. The rats presented hyperkalemia (6.9 ± 0.5 versus sham operated 4.3 ± 0.05 mEq/L, n = 6, P < 0.05) as a result of deteriorated renal function. Sections of kidneys from sham operated rats showed normal tubulointerstitium of the cortex (Figures 1A(a) and 1A(c)). In CRF rat kidneys, as previously demonstrated [8, 10, 12], diffuse fibrosis was noted in the medullary and papillary interstitium (data not shown). In the cortical interstitium, in addition to fibrosis, a substantial number of small, round cells were noted among spindle-shaped fibroblasts (Figures 1A(b) and 1A(d)). Since the mRNA expression of CD3 and ED-1, surface markers for T-lymphocytes and macrophages, was markedly elevated in the cortex isolated from CRF rat kidneys (Figure 1(B)), those round cells were considered to be inflammatory leukocytes, such as T-lymphocytes and macrophages.


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)

Histological features of sham operated (sham) and advanced CRF rat kidneys. (A) Hematoxylin and eosin staining (H&E) in sham operated (sham) and advanced CRF rat kidneys. (a) and (b) Low-power views of cortex. Magnification, ×20. (c) and (d) High-power views of cortical interstitium. Magnification, ×60. (B) The mRNA abundance of CD3 (left) and ED-1 (right) in the renal cortex of sham operated and advanced CRF (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. (C) Immunohistochemistry using antibody for Ki-67 (brown) in sham operated and advanced CRF rat kidneys. (a) and (b) High-power views of cortical interstitium. Magnification, ×60.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369525&req=5

fig1: Histological features of sham operated (sham) and advanced CRF rat kidneys. (A) Hematoxylin and eosin staining (H&E) in sham operated (sham) and advanced CRF rat kidneys. (a) and (b) Low-power views of cortex. Magnification, ×20. (c) and (d) High-power views of cortical interstitium. Magnification, ×60. (B) The mRNA abundance of CD3 (left) and ED-1 (right) in the renal cortex of sham operated and advanced CRF (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. (C) Immunohistochemistry using antibody for Ki-67 (brown) in sham operated and advanced CRF rat kidneys. (a) and (b) High-power views of cortical interstitium. Magnification, ×60.
Mentions: The marked elevation of serum creatinine (4.45 ± 1.16 versus sham operated 0.33 ± 0.03 mg/dL, n = 6, P < 0.05) and urea nitrogen (130 ± 8.95 versus sham operated 15.5 ± 1.39 mg/dL, n = 6, P < 0.05) levels in nephrectomized rats indicated advanced CRF with severe uremia [11]. The rats presented hyperkalemia (6.9 ± 0.5 versus sham operated 4.3 ± 0.05 mEq/L, n = 6, P < 0.05) as a result of deteriorated renal function. Sections of kidneys from sham operated rats showed normal tubulointerstitium of the cortex (Figures 1A(a) and 1A(c)). In CRF rat kidneys, as previously demonstrated [8, 10, 12], diffuse fibrosis was noted in the medullary and papillary interstitium (data not shown). In the cortical interstitium, in addition to fibrosis, a substantial number of small, round cells were noted among spindle-shaped fibroblasts (Figures 1A(b) and 1A(d)). Since the mRNA expression of CD3 and ED-1, surface markers for T-lymphocytes and macrophages, was markedly elevated in the cortex isolated from CRF rat kidneys (Figure 1(B)), those round cells were considered to be inflammatory leukocytes, such as T-lymphocytes and macrophages.

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