Exogenous pancreatic kininogenase protects against tacrolimus-induced renal injury by inhibiting PI3K/AKT signaling: The role of bradykinin receptors
Exogenous pancreatic kininogenase protects against tacrolimus-induced renal injury by inhibiting PI3K/AKT signaling: The role of bradykinin receptors
复制标题
DOI：
10.1016/j.intimp.2022.108547
复制
发表时间：
2022-01-20
影响因子：
5.6
通讯作者：
Li, Can
中科院分区：
文献类型：
--
作者：
Ding, Jun;Jin, Jian;Li, Can
背景：组织激肽释放酶在保护各种类型的损伤方面具有广泛的生物活性。然而，关于它在他克莫司(TAC)诱导的肾损伤中的作用的信息有限。目的：探讨胰激肽原酶(PK)对大鼠慢性TAC肾毒性的保护作用。方法：SD大鼠每日给予TAC或PK或两者合用，连续4周。从肾功能、组织病理学、细胞因子表达、氧化应激、细胞内细胞器、程序性细胞死亡和PI3K/AKT信号转导等方面观察PK对肾损伤的影响。人肾小管上皮细胞(HK-2细胞)和小鼠肾小球系膜细胞(SV40 MES13细胞)经TAC和PK处理后也进行了研究。结果：PK治疗可改善肾功能和病理组织学改变。这种作用与促炎症和促纤维化细胞因子的表达下调相平行。TAC诱导的氧化应激与内质网应激和线粒体功能障碍密切相关，导致细胞过度程序性死亡(细胞凋亡和自噬)，而PK干扰PI3K/AKT信号通路可显著消除这种过度程序性死亡。PK还能刺激缓激肽受体1(B1R)和B2RmRNA的合成，增加生物活性一氧化氮(NO)和cAMP浓度。阻断B1R或B2R均可消除PK的肾保护作用。在HK-2和SV40 MES13细胞中，PK可降低TAC诱导的细胞内氧自由基的过量产生，抑制细胞凋亡，提高细胞存活率。PK和PI3K抑制剂LY294002可抑制HK-2细胞激活的PI3K/AKT信号转导通路。结论：PK治疗通过抑制PI3K/AKT信号通路对慢性TAC肾毒性有保护作用。
Background: Tissue kallikrein offers a wide spectrum of biological activity in the protection against various types of injury. However, information on its role in tacrolimus (TAC)-induced renal injury is limited. Objectives: This study aimed to assess the beneficial effects of pancreatic kininogenase (PK) in a rat model of chronic TAC nephrotoxicity and in vitro. Methods: Sprague Dawley rats were treated daily with either TAC or PK or a combination of the two for four weeks. The influence of PK on renal injury was examined in terms of renal function, histopathology, cytokine expression, oxidative stress, intracellular organelles, programmed cell death, and PI3K/AKT signaling. Human kidney proximal tubular (HK-2) cells and mouse mesangial (SV40 MES13) cells treated with TAC and PK were also studied. Results: PK treatment improved renal function and histopathology. This effect was paralleled by downregulation of proinflammatory and profibrotic cytokine expression. TAC-induced oxidative stress was closely associated with endoplasmic reticulum stress and mitochondrial dysfunction, resulting in excessive programmed cell death (apoptosis and autophagy) that was significantly abrogated by concurrent PK interference with PI3K/AKT signaling. PK also stimulated bradykinin receptor 1 (B1R) and B2R mRNA synthesis and increased bioactive nitric oxide (NO) and cAMP concentrations in TAC-treated kidneys. Blockade of either B1R or B2R eliminated the renoprotective effects of PK. In HK-2 and SV40 MES13 cells, PK decreased TAC-induced overproduction of intracellular reactive oxygen species and inhibited apoptotic cells, whereas cell viability was improved. Moreover, activated PI3K/AKT signaling in HK-2 cells was inhibited by PK and the PI3K inhibitor, LY294002. Conclusions: These findings indicate that PK treatment protects against chronic TAC nephrotoxicity via inhibition of PI3K/AKT signaling.