Claudin-4 deficiency results in urothelial hyperplasia and lethal hydronephrosis.
Claudin-4 deficiency results in urothelial hyperplasia and lethal hydronephrosis.
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DOI：
10.1371/journal.pone.0052272
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Minato N
中科院分区：
文献类型：
--
作者：
Fujita H;Hamazaki Y;Noda Y;Oshima M;Minato N
Claudin（Cld）-4是在肾脏和泌尿道中表达的主要Cld之一，包括肾单位的选择性区段和从骨盆到膀胱的整个尿道。我们产生了Cldn 4 −/−小鼠，发现这些小鼠由于相对较晚发病的肾积水而增加了死亡率。虽然Cldn 4 −/−小鼠的肾单位显示紧密连接（TJ）处Cld 8表达的伴随减少，但TJ处Cld 3的积累在补偿中显著增强，并且整体TJ结构不受影响。尽管如此，Cld 4 −/−小鼠表现出轻微但显著增加的Ca 2+和Cl−排泄分数，表明Cld 4通过细胞旁途径在这些离子的特异性重吸收中发挥作用。虽然尿量趋于一致地增加，但Cldn 4 −/−小鼠能够在脱水时正常浓缩尿液，没有尿崩症的证据。在尿路刺激中，TJ和尿斑的形成以及总体屏障功能也不受影响。然而，静脉肾盂造影分析表明，尿流受阻之前，肾积水。组织学检查发现弥漫性增生和增厚的骨盆和输尿管尿路上皮层与体内BrdU摄取显着增加。这些结果表明，Cld 4 −/−小鼠的进行性肾积水是由尿路上皮增生引起的尿路梗阻引起的，Cld 4在维持正常尿路的稳态完整性方面起着重要作用。
Claudin (Cld)-4 is one of the dominant Clds expressed in the kidney and urinary tract, including selective segments of renal nephrons and the entire urothelium from the pelvis to the bladder. We generated Cldn4 −/− mice and found that these mice had increased mortality due to hydronephrosis of relatively late onset. While the renal nephrons of Cldn4 −/− mice showed a concomitant diminution of Cld8 expression at tight junction (TJ), accumulation of Cld3 at TJ was markedly enhanced in compensation and the overall TJ structure was unaffected. Nonetheless, Cldn4 −/− mice showed slightly yet significantly increased fractional excretion of Ca2+ and Cl−, suggesting a role of Cld4 in the specific reabsorption of these ions via a paracellular route. Although the urine volume tended to be increased concordantly, Cldn4 −/− mice were capable of concentrating urine normally on dehydration, with no evidence of diabetes insipidus. In the urothelium, the formation of TJs and uroplaques as well as the gross barrier function were also unaffected. However, intravenous pyelography analysis indicated retarded urine flow prior to hydronephrosis. Histological examination revealed diffuse hyperplasia and a thickening of pelvic and ureteral urothelial layers with markedly increased BrdU uptake in vivo. These results suggest that progressive hydronephrosis in Cldn4 −/− mice arises from urinary tract obstruction due to urothelial hyperplasia, and that Cld4 plays an important role in maintaining the homeostatic integrity of normal urothelium.
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影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
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Tsukita, Shoichiro
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15.9
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30.8
作者：
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通讯作者：
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影响因子：
64.8
作者：
FUSHIMI, K;UCHIDA, S;SASAKI, S
通讯作者：
SASAKI, S
影响因子：
3.4
作者：
Milatz, Susanne;Krug, Susanne M.;Fromm, Michael
通讯作者：
Fromm, Michael