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Article Type

Article

Abstract

Background: Renal ischemia-reperfusion injury (RIRI) constitutes a significant adverse consequence that may occur subsequent to renal transplantation, surgical interventions on the kidneys, or various pathological conditions that impair the perfusion to renal tissues. This pathological state engenders considerable injury to kidney parenchyma, which is mediated by the reparative processes. A comprehensive comprehension of transient ischemia and an investigation into the underlying mechanisms of RIRI, including oxidative stress, inflammatory responses, and cellular apoptosis pathways, are imperative for the advancement of efficacious therapeutic strategies. In this study, the efficacy of a specific Wnt activator, QS11, which facilitates the activation of the Wnt/β-catenin signaling pathway, was evaluated for its potential to mitigate renal ischemia-reperfusion injury (RIRI) in an experimental rat model. For the purposes of this investigation, the rat subjects were allocated into six distinct cohorts: a sham group that was not subjected to RIRI, an untreated RIRI control group, a vehicle 1 RIRI group corresponding to QS11, a vehicle 2 RIRI group for tideglusib, and two treatment groups that were administered QS11 and tideglusib, respectively. Aim of study: The objective of this research was to evaluate the renoprotective effects of QS11 through the activation of the Wnt/β-catenin signaling pathway in a rat model exhibiting acute kidney injury induced by ischemia-reperfusion. Methodology: Prior to the administration of anesthesia, rats were permitted a period of acclimatization, followed by a midline laparotomy to facilitate the exposure of the renal pedicles. The renal blood supply was intentionally occluded for a duration of thirty minutes, after which the obstruction was alleviated to restore blood flow (reperfusion). A noticeable alteration in the pigmentation of the kidneys provided visual confirmation of the occurrence of reperfusion. Subsequent to a ninety-minute interval, blood samples were collected for the evaluation of kidney injury molecule-1, a recognized biomarker indicative of renal functionality. The assessment of renal tissue involved the application of PCR to quantify the activation of the WNT β-CATENIN signaling pathway. Additionally, indicators of cellular apoptosis, specifically caspase-3, along with inflammatory mediators such as TNF-α, IL-1, and IL-6, in conjunction with various antioxidative agents (Nrf2, HO-1) associated with tissue injury, were quantified utilizing the ELISA technique. Result: The capacity of QS11 to enhance the wnt β-catenin signaling pathway has been demonstrated to substantially mitigate renal ischemia-reperfusion injury (RIRI) in comparison to the control cohort. The documented protective effect was ascribed to the pharmacological intervention, as evidenced by the significantly diminished levels of β-catenin and cyclin D1 in the sham group relative to all other experimental groups (p < 0.05). In contrast to the RIRI cohort, which denotes the translocation of catenin molecules from the cytoplasm to the nucleus, the QS11-treated group exhibited markedly reduced concentrations of pro-proliferative factors (β-catenin and cyclin D1), which are instrumental in activating the β-catenin signaling cascade within the renal tissue, thereby facilitating cellular proliferation, differentiation, and regeneration, ultimately culminating in the restoration of acute renal function. Nevertheless, this pharmacological agent (QS11) demonstrated a protective role against apoptosis, or programmed cell death. When juxtaposed with the control group exhibiting RIRI, the sham group displayed reduced levels of caspase-3, a pro-apoptotic mediator. Furthermore, the sham group exhibited diminished levels of the NFκB mediator compared to the control group with RIRI. Additionally, the QS11-treated cohort presented lower concentrations of both caspase-3 and NFκB in comparison to the control group with RIRI. Our investigation revealed that the QS11-treated cohort exhibited significantly reduced levels of inflammatory biomarkers (TNF-α, IL-1, and IL-6) in contrast to the control group with RIRI. Moreover, the sham group demonstrated significantly lower levels of these inflammatory biomarkers compared to the control group with RIRI (p < 0.05). Furthermore, this study illustrated that the QS11-treated cohort possessed elevated levels of anti-oxidative markers (Nrf2, HO-1) when compared to the control group with RIRI, indicating a notable stimulatory effect on the oxidative response. In addition, KIM-1 (a marker of renal injury) was significantly diminished in the QS11-treated cohort, indicating improved renal function. The histological assessment of the renal tissue in the sham group elucidated normal renal architecture. The vehicle and control groups, however, experienced significant, predominantly severe, renal damage. In contrast, the renal injury observed in the control groups was notably mitigated by QS11 therapy. Conclusion: By stimulating the wnt β-catenin signaling pathway system, QS11 exhibits nephro-protective characteristics by lowering inflammatory marker levels, lowering kim factor, raising Nrf2, HO-1, and lowering apoptosis. Potentially, this medication could be a unique treatment forrenal ischemia reperfusion injur(RIRI).

Keywords

QS11, Wnt/β-catenin signaling, Tideglusib

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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