Role of ERK signaling in bladder urothelium in response to cyclophosphamide injury.
Role of ERK signaling in bladder urothelium in response to cyclophosphamide injury.
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ERK信号通路在环磷酰胺致膀胱尿路上皮损伤中的作用
DOI：
10.14814/phy2.15378
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发表时间：
2022-07
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
用环磷酰胺损伤的具有成纤维细胞生长因子受体2（ShhCreERT 2; Fgfr 2 Fl/Fl）的可诱导尿路上皮缺失的小鼠具有异常的基底细胞内复制和差的再生。内复制与磷酸化（激活）ERK表达的情况下，尿路上皮。我们评估了抑制ERK活性是否表型模仿了损伤的Fgfr 2突变小鼠的尿路上皮缺陷。我们在小鼠中全身性联合给予环磷酰胺和ERK抑制剂（ERKi），并评估损伤后各种标志物的一般组织学和免疫荧光。由于AKT也在FGFR 2的下游信号传导，我们评估了AKT抑制剂（AKTi）对环磷酰胺损伤的影响。ERK敲低不影响环磷酰胺后24小时尿路上皮损伤或增殖。相反，与溶媒处理的小鼠相比，ERK抑制导致损伤后3天基底细胞核更大，粘膜下出血更多，尿斑蛋白染色减弱。与溶剂处理的小鼠相比，ERKi处理的小鼠具有更多Ki 67+尿路上皮细胞的趋势，并且具有统计学上更少的归一化为Ki 67的磷酸化组蛋白H3+细胞和更高的基底细胞DNA含量，与损伤后3天的内复制一致。损伤后10天，ERKi处理的小鼠仍然具有尿路上皮再生不良的迹象，分化标志物表达缺失或异常，以及角蛋白14（基础祖细胞标志物）的异位管腔表达。在环磷酰胺给药后3天，AKTi联合给药未导致明显的尿路上皮缺损。因此，ERK敲低（而不是AKT敲低）导致环磷酰胺后的尿路上皮再生反应，让人想起Fgfr 2突变小鼠。总之，似乎FGFR 2通过ERK起作用以防止异常的尿路上皮基底细胞内复制并确保环磷酰胺后的正常再生。小鼠尿路上皮中成纤维细胞生长因子受体2的缺失导致病理性内复制和环磷酰胺后修复不良。敲低ERK的小鼠对环磷酰胺具有类似的病理学反应，而敲低AKT不会导致缺陷。因此，FGFR 2可能通过ERK信号传导抑制尿路上皮对环磷酰胺的适应不良反应。
Mice with inducible urothelial deletion of fibroblast growth factor receptor 2 (ShhCreERT2;Fgfr2 Fl/Fl ) injured with cyclophosphamide had aberrant basal cell endoreplication and poor regeneration. The endoreplication correlated with an absence of phosphorylated (activated) ERK expression in urothelium. We assessed whether inhibiting ERK activity phenocopied the urothelial defects in injured Fgfr2 mutant mice. We co‐administered cyclophosphamide and an ERK inhibitor (ERKi) systemically in mice and assessed general histology and immunofluorescence for various markers post injury. Since AKT also signals downstream of FGFR2, we assessed effects of an AKT inhibitor (AKTi) on cyclophosphamide injury. ERK knockdown did not affect urothelial injury or proliferation 24 h after cyclophosphamide. Conversely, ERK inhibition led to larger basal cell nuclei, more submucosal hemorrhage and attenuated uroplakin staining 3 days after injury versus vehicle‐treated mice. Compared to vehicle‐treated mice, ERKi‐treated mice had a trend for more Ki67+ urothelial cells and had statistically fewer phospho‐Histone H3+ cells normalized to Ki67 and higher basal cell DNA content, consistent with endoreplication 3 days after injury. Ten days after injury, ERKi‐treated mice still had signs of poor urothelial regeneration with absent or aberrant expression of differentiation markers and ectopic lumenal expression of keratin 14 (basal progenitor marker). Co‐administration of the AKTi led to no apparent urothelial defects 3 days after cyclophosphamide. Thus, ERK knockdown (but not AKT knockdown) leads to urothelial regenerative responses after cyclophosphamide reminiscent of Fgfr2 mutant mice. Together, it appears that FGFR2 acts through ERK to prevent aberrant urothelial basal cell endoreplication and ensure normal regeneration after cyclophosphamide. Deletion of fibroblast growth factor receptor 2 in mouse urothelium leads to pathological endoreplication and poor repair after cyclophosphamide. Mice with knockdown of ERK have a similar pathological response to cyclophosphamide while knockdown of AKT causes no defects. Thus FGFR2 likely signals via ERK to suppress urothelial maladaptive responses to cyclophosphamide.
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影响因子：
10.5
作者：
LaBaer, J;Garrett, MD;Harlow, E
通讯作者：
Harlow, E
影响因子：
7.2
作者：
Belov AA;Mohammadi M
通讯作者：
Mohammadi M
DOI：
10.1073/pnas.95.9.5082
发表时间：
1998-04-28
影响因子：
11.1
作者：
Arman, E;Haffner-Krausz, R;Lonai, P
通讯作者：
Lonai, P
影响因子：
6.4
作者：
KALDOR, JM;DAY, NE;BOFFETTA, P
通讯作者：
BOFFETTA, P
影响因子：
30.3
作者：
Mysorekar IU;Isaacson-Schmid M;Walker JN;Mills JC;Hultgren SJ
通讯作者：
Hultgren SJ