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Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.

ABSTRACT: 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.

SUBMITTER: Abousaad S

PROVIDER: S-EPMC9483619 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.

Abousaad Shaymaa S Ahmed Faihaa F Abouzeid Ayman A Ongeri Elimelda Moige EM

Physiological reports 20220901 18

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 i ...[more]

PMID: 36117389

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Project description:Hepatic ischemia-reperfusion (IR) injury is a clinical issue that can result in poor outcome and lacks effective therapies at present. Mild hypothermia (32-35°C) is a physiotherapy that has been reported to significantly alleviate IR injury, while its protective effects are attributed to multiple mechanisms, one of which may be the regulation of fatty acid β-oxidation (FAO). The aim of the present study was to investigate the role and underlying mechanisms of FAO in the protective effects of mild hypothermia. We used male mice to establish the experimental models as previously described. In brief, before exposure to in situ ischemia for 1 h and reperfusion for 6 h, mice received pretreatment with mild hypothermia for 2 h and etomoxir (inhibitor of FAO) or leptin (activator of FAO) for 1 h, respectively. Then, tissue and blood samples were collected to evaluate the liver injury, oxidative stress, and changes in hepatic FAO. We found that mild hypothermia significantly reduced the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury. In addition, the expression of the rate-limiting enzyme (CPT1a) of hepatic FAO was downregulated almost twofold by IR, while this inhibition could be significantly reversed by mild hypothermia. Experiments with leptin and etomoxir confirmed that activation of FAO could also reduce the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury induced by IR, which had the similar effects to mild hypothermia, while inhibition of FAO had negative effects. Furthermore, mild hypothermia and leptin could promote the phosphorylation of JAK2/STAT3 and upregulate the ratio of BCL-2/BAX to suppress hepatocyte apoptosis. Thus, we concluded that FAO played an important role in hepatic IR injury and mild hypothermia attenuated hepatic IR injury mainly via the regulation of JAK2/STAT3-CPT1a-dependent FAO.

Project description:Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process.Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses.Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 μmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA.BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.

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Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.

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Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury.

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