Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E
Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E
复制标题
Gsa 的消融通过 CDK2/cyclin E 损害损伤后的肾小管增殖
DOI：
10.1152/ajprenal.00367.2019
复制
发表时间：
2020-03-01
影响因子：
4.2
通讯作者：
Xu，Gang
中科院分区：
文献类型：
--
作者：
Liu，Lele;Deng，Yuanjun;Xu，Gang
急性肾损伤具有与死亡和慢性肾脏疾病风险增加相关的高全球发病率。损伤后肾小管上皮细胞的再生可能是肾脏修复或急性肾损伤进展为慢性肾脏疾病的决定性因素，但肾小管修复异常的潜在机制仍不清楚。本研究探讨了异三聚体G刺激蛋白α亚基（Gsa）在肾小管上皮细胞再生中的作用。我们产生了肾小管上皮特异性Gsa敲除（GsaKspKO）小鼠，以显示Gsa在两种阿基模型（急性马兜铃酸肾病（AAN）和单侧缺血再灌注损伤（UIRI））中肾小管上皮细胞再生中的重要作用。与野生型小鼠相比，GsaKspKO小鼠在AAN和UIRI后发生了更严重的肾损伤、更高的血清肌酐水平和更多的实质性肾小管坏死。更重要的是，Gsa失活通过减少AAN模型中的溴脱氧尿苷+细胞数量和抑制UIRI模型中的细胞周期蛋白依赖性激酶2/细胞周期蛋白E1表达来损害肾小管上皮细胞增殖。这种降低的增殖在体外进一步得到Gsa靶向siRNA的支持。下调Gsa可抑制HK-2和mIMCD-3细胞中肾小管上皮细胞的增殖。此外，Gsa下调抑制细胞周期蛋白依赖性激酶2/细胞周期蛋白E1的表达，这是依赖于Raf-MEK-ERK信号通路。总之，Gsa是阿基后肾修复过程中肾小管上皮细胞再生所必需的。Gsa的缺失通过阻断Raf-MEK-ERK途径损害肾小管上皮细胞再生。
Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKOmice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.