Lentivirus-Mediated Silencing of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 Inhibits Release of Inflammatory Cytokines and Apoptosis in Renal Tubular Epithelial Cells Via Inhibition of the TLR4/NF-kB Pathway in Renal Ischemia-Reperfusion Injury

Abstract

Background/Aims: Renal reperfusion injury occurs after the blood flow to the ischemic kidney is re-established under various clinical conditions, such as organ transplantation, renal artery stenosis, embolic disease, and the repair of descending aortic. The current study aims to explore the effects of src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) on the release of inflammatory cytokines and the apoptosis of renal tubular epithelial cells by regulating the TLR4/NF-κB signaling pathway in rats with renal ischemia-reperfusion (I/R) injury. Methods: A total of 60 normal clean Sprague Dawley (SD) (WT) rats were used in this study. The levels of creatinine (Cr) and blood urea nitrogen (BUN) were determined using an automatic biochemical analyzer. The apoptosis in renal tissue was detected by TUNEL assay. The renal tubular epithelial cells of rats were cultured, infected and treated with different lentivirus vectors. The serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β and SHP27 were measured. Reverse transcription quantitative polymerases chain reaction and Western blot analysis were performed to measure the expression of relevant genes and proteins. Furthermore, the effect of SHP-2 on the proliferation, cell cycle and apoptosis of renal tubular epithelial cells was also investigated. Results: In the serum of rats with renal I/R injury and prolonged reperfusion time, the contents of Cr and BUN were increased, the positive expression of SHP-2 was higher, the level of apoptosis was promoted, IL-6, TNF-α, IL-1β and SHP27 expression in the serum was increased, the expression of SHP2, TLR4, NF-κB, IL-6, TNF-α and Bax was up-regulated, and the expression of Bcl-2 was down-regulated. Lentivirus-mediated silencing of SHP-2 promoted the proliferation of renal tubular epithelial cells, inhibited their apoptosis, and reduced the expression of inflammatory factors in these cells by functionally suppressing the TLR4/NF-κB signaling pathway. Conclusion: The results indicated that lentivirus-mediated silencing of SHP-2 inhibited the release of inflammatory cytokines and the apoptosis of renal tubular epithelial cells, and promoted the proliferation of these cells by inhibiting the TLR4/NF-κB signaling pathway in rats with renal I/R injury.

Toll-Like Receptors in Acute Kidney Injury

“…SHP2 knockout in myeloid cells protected the kidneys from inflammatory damage and prevented renal fibrosis after unilateral ureter obstruction [130]. SHP2 deficiency also had a protective effect in renal ischemia-reperfusion [131]. SHP2 is assumed to have an additional role as an antagonist of TBK1 beyond its phosphatase activity [104,105].…”

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model

“…Previous studies have revealed that select inflammatory signaling pathways are involved in the processes driving AKI. Teng et al showed that the lentivirus-mediated silencing of SHP2 improved I/R-induced AKI via inhibition of the TLR4/NF-kB Pathway (Teng et al 2018 ). Chen et al revealed that the PHPS1 exerted a protective effect against atherosclerosis via suppression of the SHP2:ERK pathway activation (Chen et al 2018 ).…”

“…We recently reported that SHP1, but not SHP2, reduces PD-L1-dependent regulation of T regulatory lymphocyte (Treg) function and is associated with resolution of shock- and sepsis-induced lung injury (Tang et al 2015 ). Additionally, previous research has demonstrated that SHP2 deficiency may have a protective effect in experimental renal (Hsu et al 2017 ; Teng et al 2018 ; Verma et al 2016 ) and cardiovascular (Chen et al 2018 ) injury. Thus, it appears that SHP2 activation may have differential effects depending on the location of action.…”

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

“…Previous studies have revealed that select inflammatory signaling pathways are involved in the processes driving AKI. Teng et al (Teng, et al 2018) showed that the lentivirus-mediated silencing of SHP2 improved I/R-AKI via inhibition of the TLR4/NF-kB Pathway. Chen et al revealed that the SHP2 inhibitor PHPS1 exerted a protective effect against atherosclerosis via suppression of the SHP2:ERK pathway activation.…”

“…We recently reported that SHP1, but not SHP2, negatively modulated PD-L1 dependent regulation of T regulatory lymphocyte (Treg) function and in so doing contributed to resolving shock/sepsis-induced lung injury (Tang et al 2015). At the same time, some studies have revealed that SHP2 deficiency may have a protective effect in experimental renal (Hsu et al 2017, Teng et al 2018, Verma et al 2016) and cardiovascular (Chen et al 2018) conditions. Thus, SHP2 activation may play distinct roles in different organs.…”