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首页> 外文期刊>American Journal of Physiology >Meprin-beta activity modulates the beta-catalytic subunit of protein kinase A in ischemia-reperfusion-induced acute kidney injury.
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Meprin-beta activity modulates the beta-catalytic subunit of protein kinase A in ischemia-reperfusion-induced acute kidney injury.

机译：Meprin-β活性调节蛋白激酶A的β-催化亚基，在缺血再灌注诱导的急性肾损伤中。

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摘要

Meprin metallo-proteases have been implicated in the progression of kidney injury. Previous work from our group has shown that meprins proteolytically process the catalytic subunit of protein kinase A (PKA-C), resulting in decreased PKA-C kinase activity. The goal of the present study was to determine the PKA-C isoforms impacted by meprin-beta and whether meprin-beta expression affects downstream mediators of the PKA signaling pathway in ischemia-reperfusion (IR)-induced kidney injury. IR was induced in 12-wk-old male wild-type (WT) and meprin-p knockout (PKO) mice. Madin-Darby canine kidney cells transfected with meprin-P cDNA were also subjected to 2 h of hypoxia. Western blot analysis was used to evaluate levels of total PKA-C, PKA-Calpha, PKA-CP, phosphorylated (p-)PKA-C, and p-ERK1/2. Meprin-beta expression enhanced kidney injury as indicated by levels of neutrophil gelatinase-associated lipocalin and cystatin C. IR-associated decreases were observed in levels of p-PKA-C in kidney tissue from WT mice but not betaKO mice, suggesting that meprin-beta expression/activity is responsible for the in vivo reduction in kinase activity. Significant increases in levels of PKA-Cp were observed in kidney lysates for WT mice but not pKO mice at 6 h post-IR. Proximal tubule PKA-Cbeta increases in WT but not betaKO kidneys were demonstrated by fluorescent microscopy. Furthermore, IR-induced injury was associated with significant increases in p-ERK levels for both genotypes. The present data demonstrate that meprin-P enhances IR-induced kidney injury in part by modulating mediators of the PKA-Cbeta signaling pathway.
机译：Meprin金属蛋白酶涉及肾损伤的进展。我们本集团的以往的工作表明，兆蛋白蛋白质解除蛋白激酶A（PKA-C）的催化亚基，导致PKA-C激酶活性降低。本研究的目的是确定受MEPRIN-β影响的PKA-C同种型，以及MEPRIN-β表达是否影响PKA信号通路的下游介质在缺血再灌注（IR）诱导的肾损伤中。 IR诱导12-WK老雄性野生型（WT）和Meprin-P淘汰赛（PKO）小鼠。用Meprin-P-P cDNA转染的Madin-Darby犬肾细胞也经受缺氧2小时。 Western印迹分析用于评估PKA-C，PKA-CALPHA，PKA-CP，磷酸化（P-）PKA-C和P-ERK1 / 2的水平。 Meprin-β表达增强的肾损伤，如嗜中性粒细胞凝胶酶相关的脂素水平和胱抑素C.从WT小鼠的肾脏组织中的P-PKA-C水平观察到IR相关的降低，但不是Betako小鼠，表明Meprin- β表达/活性负责激酶活性的体内降低。在WT小鼠的肾裂解物中观察到PKA-CP水平的显着增加，但在IR后6小时，不是PKO小鼠。 WT的近端小管PKA-CBETA增加但不通过荧光显微镜证明Betako肾脏。此外，IR诱导的损伤与两种基因型的P-ERK水平显着增加有关。本数据表明，通过调节PKA-CBETA信号通路的介质，Meprin-P部分提高了IR诱导的肾损伤。

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