Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.
Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.
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Meprin β表达调节白细胞介素-6介导的JAK2-STAT3信号通路在缺血/再灌注肾损伤中的作用
DOI：
10.14814/phy2.15468
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发表时间：
2022-09
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
Meprin金属蛋白酶与缺血/再灌注（IR）诱导的肾损伤的病理生理有关。先前的体外数据表明，meprin β蛋白水解白介素- 6 （IL - 6）导致其失活。最近，meprin‐β也被证明可以切割IL‐6受体。本研究的目的是确定meprin β表达在IR诱导的肾损伤中如何影响IL - 6和JAK2 - STAT3介导的信号通路的下游调节剂。IR在12周龄雄性野生型（WT）和meprin β敲除（β ko）小鼠和IR后24小时获得的肾脏中诱导。采用实时PCR、western blot和免疫染色/显微镜方法分别定量mRNA和蛋白质水平，并使用近端小管（PT）标记进行免疫荧光反染色以确定蛋白质定位。IL - 6、CASP3和BCL - 2 mRNA水平在两种基因型中均显著升高。有趣的是，western blot数据显示，βKO中IL - 6、CASP3和BCL - 2蛋白水平升高，而WT肾脏中没有。然而，免疫组织化学数据显示，两种基因型肾小管中IL - 6、CASP3和BCL - 2蛋白均升高，免疫荧光反染色显示为PTs。IR诱导βKO中p‐STAT‐3和p‐JAK‐2在全球水平上增加，但免疫荧光反染色显示两种基因型的PT中p‐JAK2和p‐STAT3增加。BCL‐2仅在WT肾的肾小体中升高，提示meprins在白细胞中表达的作用。免疫组织化学分析证实，与βKO肾脏相比，WT肾脏的白细胞浸润水平更高。目前的数据表明，meprin β在一定程度上通过IL - 6/JAK2/STAT3介导的信号传导调节IR诱导的肾损伤。Meprin金属蛋白酶与急性和慢性肾脏疾病有关。目前的研究表明，在缺血/再灌注诱导的肾损伤中，meprin β的表达与高水平的白细胞介素- 6蛋白相关。在IL‐6的下游，meprin β影响JAK‐STAT3介导的信号通路和凋亡基因CASP3和BCL‐2。
Meprin metalloproteinases have been implicated in the pathophysiology of ischemia/reperfusion (IR)‐induced kidney injury. Previous in vitro data showed that meprin β proteolytically processes interleukin‐6 (IL‐6) resulting in its inactivation. Recently, meprin‐β was also shown to cleave the IL‐6 receptor. The goal of this study was to determine how meprin β expression impacts IL‐6 and downstream modulators of the JAK2‐STAT3‐mediated signaling pathway in IR‐induced kidney injury. IR was induced in 12‐week‐old male wild‐type (WT) and meprin β knockout (βKO) mice and kidneys obtained at 24 h post‐IR. Real‐time PCR, western blot, and immunostaining/microscopy approaches were used to quantify mRNA and protein levels respectively, and immunofluorescence counterstaining with proximal tubule (PT) markers to determine protein localization. The mRNA levels for IL‐6, CASP3 and BCL‐2 increased significantly in both genotypes. Interestingly, western blot data showed increases in protein levels for IL‐6, CASP3, and BCL‐2 in the βKO but not in WT kidneys. However, immunohistochemical data showed increases in IL‐6, CASP3, and BCL‐2 proteins in select kidney tubules in both genotypes, shown to be PTs by immunofluorescence counterstaining. IR‐induced increases in p‐STAT‐3 and p‐JAK‐2 in βKO at a global level but immunoflourescence counterstaining demonstrated p‐JAK2 and p‐STAT3 increases in select PT for both genotypes. BCL‐2 increased only in the renal corpuscle of WT kidneys, suggesting a role for meprins expressed in leukocytes. Immunohistochemical analysis confirmed higher levels of leukocyte infiltration in WT kidneys when compared to βKO kidneys. The present data demonstrate that meprin β modulates IR‐induced kidney injury in part via IL‐6/JAK2/STAT3‐mediated signaling. Meprin metalloproteases are implicated in acute and chronic kidney disease. The current study shows that meprin beta expression associates with high levels of interleukin‐6 proteins in ischemia/reperfusion‐induced kidney injury. Downstream of IL‐6, meprin beta impacts the JAK‐STAT3 mediated signaling pathway and the apoptotic genes CASP3 and BCL‐2.
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影响因子：
19.6
作者：
Han SJ;Williams RM;D'Agati V;Jaimes EA;Heller DA;Lee HT
通讯作者：
Lee HT
影响因子：
--
作者：
Bedau T;Schumacher N;Peters F;Prox J;Arnold P;Koudelka T;Helm O;Schmidt F;Rabe B;Jentzsch M;Rosenstiel P;Sebens S;Tholey A;Rose-John S;Becker-Pauly C
通讯作者：
Becker-Pauly C
DOI：
10.1152/ajprenal.00179.2012
发表时间：
2013-09-01
影响因子：
4.2
作者：
Bao, Jialing;Yura, Renee E.;Bond, Judith S.
通讯作者：
Bond, Judith S.
影响因子：
20.3
作者：
Chakraborty, A;White, SM;Tweardy, DJ
通讯作者：
Tweardy, DJ
影响因子：
82.9
作者：
Atreya, R;Mudter, J;Neurath, MF
通讯作者：
Neurath, MF