Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion‐induced injury through the B2R‐Raf‐MEK1/2‐ERK1/2 pathway

Abstract

We have documented that tissue kallikrein (TK) prevents neurons from hypoxia/reoxygenation injury through the B2R-ERK1/2 pathway and the antihypoxic function of TK through Homer1b/c-ERK1/2 signaling pathways. The present study investigates the molecular mechanisms of exogenous TK activation of the B2R-ERK1/2 pathway through the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module in vivo. The cresyl violet staining results indicated that exogenous TK protected the rat hippocampal CA1 neurons against cerebral ischemia/reperfusion (I/R) injury. The immunoprecipitation (IP) and immunoblotting (IB) results revealed that exogenous TK upregulated the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and upregulated the phosphorylation of Raf (p-Raf), MEK1/2 (p-MEK1/2), and ERK1/2 (p-ERK1/2). Meanwhile, exogenous TK upregulated the expression of nuclear factor-κB (NF-κB), depressed the release of cytochrome c (Cyt c) and bax from mitochondria to the cytosol, and depressed the activation of caspase-3. Take together, our results suggest that exogenous TK attenuated the cerebral I/R induced rat hippocampal CA1 neurons injury through activating the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and that the activated B2R-Raf-MEK1/2 signaling module could upregulate the expression of NF-κB, decrease the release of cytochrome c and bax from mitochondria to the cytosol, and depress the activation of caspase-3.

PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB

“…In addition, H/R activates MAPKs, nuclear factor jB (NFjB), and hypoxiainducible factor 1a (HIF1a) that contribute to inflammation and revascularization, thus causing serious problems in the retina. 21,22 In this study, we used a rat model in which 2 weeks of retinal hypoxia resulting from systemic hypoxia was established, followed by 2 weeks of reoxygenation. This chronic model provided a better simulation of the conditions of disease development than those of most previous studies and represented a reliable method for simulating hypoxia-related disease processes.…”

The Mechanism of Ischemic Preconditioning Up-Regulation the Expression of Tissue Kallikrein Protects Neurons from Cerebral Ischemia/Reperfusion Injury

“…Recent studies have shown that exogenous TK could prevent I/R-induced neuronal injury via the B2R-ERK1/2 pathway [10,32]. Our latest research results also show that exogenous TK can activate ERK1/2 and its downstream mitochondrial pathway through activation of the β-arrestin-2 assembled B2R-Raf-MEK1/2 signalling module [16]. To explore the signalling pathway of endogenous TK, we investigated the related activation of signal factors after IP.…”

“…It has also been shown that ERK1/2 signalling can affect cell apoptosis and survival through mitochondrial and nuclear pathways. In addition, our previous studies have found that exogenous TK can activate ERK1/2 and its downstream mitochondrial and nuclear pathways through activation of the β-arrestin-2 assembled B2R-Raf-MEK1/2 signalling module [16]. In this experiment, we further explored the possible signalling pathway of endogenous TK.…”

Tissue kallikrein promotes survival and β-catenin degradation in SH-SY5Y cells under nutrient stress conditions via autophagy

“…Tissue kallikrein (TK), an important component of the kallikrein-kinin system, belongs to a sub-group of serine proteinases and processes low-molecular-weight kininogen to release kinin peptide (2). Previous studies by our group showed that TK exerted neuroprotective effects in oxygen-glucose-deprived cells as well as in the ischemic brain (3)(4)(5), in which autophagy has been reported to have an important role in maintaining neuronal survival (6). It has been reported that TK is able to activate the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway (4) and adenosine 5'-monophosphate-activated protein kinase phosphorylation (7), which participate in autophagy induction (8,9).…”