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  • Our animal model of CLP induced AKI provided direct


    Our animal model of CLP-induced AKI provided direct evidence of the relationship between TIMP2 and renal function. In mice, TIMP2-specific knockdown in the kidney through injections of lentiviral vectors provided a safe and efficient method for the genetic manipulation of renal tubules, thus representing a rapid and versatile alternative to genetically engineered mice for the functional characterization of disease-related genes [41]. Lentiviral vectors are particularly promising candidates because they have the ability to infect nonproliferating CORM-3 and to integrate into the genome of host cells, thereby achieving long-term transduction. Because of the slow turnover of renal cells in general, lentiviral vectors may be ideal candidates for renal gene therapy. IL-1β, IL-6, and TNF-α levels were decreased in the TIMP2 knockdown mice after CLP. The silencing of TIMP2 reduced kidney cell apoptosis percentage and decreased phosphorylation of P65. Kidney morphology and function were also ameliorated in TIMP2 knockdown mice. These results demonstrate that downregulation of TIMP2 could attenuate kidney inflammation and injury, thus suggesting that TIMP2 gene transfer into the kidney could be a novel therapeutic approach.
    Strength and limitation Our study has numerous strengths. Chief among these are the use of both in vitro and in vivo models involving 2 different species (human and mouse). To our knowledge the present study is the first study to show that TIMP2 is a mediator of AKI and not merely a marker. However, there were some limitations of our study. First, we could not assess survival changes with the modulation of TIMP2, as we had to sacrifice the animals early to collect tissues. Secondly, we studied only the NF-κB pathway, as it was the most important pathway to regulate the inflammatory response. It remains unknown whether other pathways also play important roles in TIMP2 signaling. Further studies are needed to understand this aspect.
    Conclusion In summary, we explored the possible roles of TIMP2 in septic AKI and found that TIMP2 does indeed promote kidney damage apparently by acting on NF-κb. We hypothesize a feedback loop that promotes apoptosis and leads to AKI (Fig. 7). On the contrary, suppressing TIMP2 protects against kidney damage, reduces p-P65 activity, attenuates proinflammatory cytokines, improves cell viability, and reduces apoptosis. Our results reveal a potential new therapeutic target for AKI in the setting of sepsis and possibly other conditions.
    Competing interests
    Funding This work was supported by the National Natural Science Foundation of China (No. 81772046, No. 81560131); Hubei Province Technology and Innovation Project (Foreign collaboration of Science and Technology) (No. 2017AHB044); Health Commission of Hubei province (No. WJ2017Z008).
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    Introduction Bone cancer pain (BCP) is the pain induced by primary bone cancer or tumor metastasis [1]. Bone metastasis arises more commonly in patients with breast, prostate, kidney and lung cancers. When tumor cells begin to grow in bone, tumor growth causes bone destruction, woven bone formation, and a significant bone pain [2]. BCP is usually described as dull in character, constant in presentation, and gradually intensifies to severe incident pain, which debilitates the quality of patients' life and their functional status [3]. Pathology of BCP is complex and unique, mixing with inflammatory, neuropathic pain and tumor-specific mechanisms [4]. Despite a variety of factors are linked to bone cancer pain, the specific cellular and molecular mechanisms underlie the pathogenesis of bone cancer pain remain unclear, and the effective clinical approaches are needed for its treatment. To date the therapeutic avenue for BCP are pharmacotherapy and chemotherapeutics. The mainstay symptomatic treatment for bone cancer pain is opioid-based pharmacotherapy, but the limited effectiveness and side-effects prohibit the widespread use of the drugs [5,6]. Non-steroidal anti-inflammatory drugs treatment is helpful, but with gastrointestinal, cardiovascular and renal risk [7]. Consequently, further research is needed to develop more effective strategies and treatment based on the different mechanisms of BCP.