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Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition.

ABSTRACT: Unilateral ureteral obstruction (UUO) induces functional and pathological changes in the obstructed kidney. Inducible nitric oxide synthase (iNOS) expression is high inearly UUO mouse kidney, which is accompanied with fibrosis. Propofol has preventive effects against renal injury by downregulating iNOS expression in UUO mouse models. However, the role of propofol in kidney fibrosis progression has not been reported. We explored the therapeutic potential and possible mechanisms of action of propofol in kidney fibrosis using a UUO mouse model. Herein, mice anesthetized with propofol or sevoflurane underwent UUO induction. Serum and kidney sections were collected 5 and 28 days post-operation for histological, morphometric, immunofluorescence, microRNA analyses; quantitative PCR and western blotting. In vivo, the effect and mechanism of propofol on epithelial-mesenchymal transition (EMT), transforming growth factor ? (TGF-?) signaling and miR-155 levels were detected in cultured HK-2 cells. We found that propofol significantly suppressed UUO-induced kidney fibrosis, which was associated with TGF-?/Smad3 signaling, EMT, and iNOS-NO production. MiR-155 levels were higher in UUO mouse kidneys; compared with sevoflurane, propofol suppressed miR-155 levels. However, in late UUO, propofol could not prevent kidney fibrosis or suppress EMT and miR-155. The in vitro results showed that propofol suppressed TGF-?1-induced EMT by regulating miR-155 levels. As a conclusion, in early UUO mice, propofol may inhibit TGF-?1 expression and NO-iNOS production, consequently inhibiting EMT and kidney fibrosis by regulating miR-155 levels, and might be a new protective agent against kidney injury during surgery and in therapy to prevent kidney fibrosis.

SUBMITTER: Song L

PROVIDER: S-EPMC4846896 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition.

Song Li L Shi Sen S Jiang Wei W Liu Xueru X He Yanzheng Y

American journal of translational research 20160215 2

Unilateral ureteral obstruction (UUO) induces functional and pathological changes in the obstructed kidney. Inducible nitric oxide synthase (iNOS) expression is high inearly UUO mouse kidney, which is accompanied with fibrosis. Propofol has preventive effects against renal injury by downregulating iNOS expression in UUO mouse models. However, the role of propofol in kidney fibrosis progression has not been reported. We explored the therapeutic potential and possible mechanisms of action of propo ...[more]

PMID: 27158339

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Project description:Although the primary organ has been the subject of intense investigation in the field of organ fibrosis over the past several decades, the presence of lymph node fibrosis due to persistent activation of the immune response in its partner organ remains largely unknown. Previously, we demonstrated that activation of the immune response following ischemia-reperfusion injury (IRI) and crescentic glomerulonephritis (CGN) in the kidney was associated with extracellular matrix (ECM) production by fibroblastic reticular cells (FRCs) of the kidney-draining lymph node (KLN). Here, we sought to determine whether FRCs in the KLN become similarly fibrogenic following unilateral ureteral obstruction (UUO) of the kidney. We subjected 6-8-week-old C57BL/6J mice to UUO for 2, 7, and 14 days. We examined the microarchitecture of the kidney and KLN by immunofluorescence staining at each timepoint, and we quantified immune cell populations in the KLN by flow cytometry. The contralateral kidney unaffected by UUO and its partner KLN were used as controls. We found through immunofluorescence staining that FRCs increased production of ECM fibers and remodeled the microarchitecture of the UUO KLN, contributing to fibrosis that mirrored the changes in the kidney. We also observed by flow cytometry that the populations of CD11b+ antigen-presenting cells, CD11c+ dendritic cells, and activated CD4+ and CD8+ T cells were significantly higher in the UUO KLN than the KLN draining the unaffected contralateral kidney. Expression of the TGFβ/TGFβR signaling pathway was upregulated and colocalized with FRCs in the UUO KLNs, suggesting a possible mechanism behind the fibrosis. Both release of ureteral ligation at 2 days following UUO and depletion of FRCs at the time of injury onset halted the progression of fibrosis in both the kidney and the KLN. These findings for the first time highlight the association between fibrosis both in the kidney and the KLN during UUO, and they lay the groundwork for future studies that will investigate more deeply the mechanisms behind the connection between FRCs and KLN fibrosis.

Dataset Information

Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition.

Publications

Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition.

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