대한신장학회

논문분류	춘계학술대회 초록집
제목	Inhibition of STAT3 in T lymphocytes and tubular epithelial cells protects against renal ischemia-reperfusion injury
저자	Seung Hee Yang1, Jae Wook Lee* 2, Ji In Park3, Ran-Hui Cha4, Jung Pyo Lee5, Kyung Don Yoo6, Yon Su Kim7
출판정보	2016; 2016(1):
키워드	Ischemia-Reperfusion Injury, STAT3, Th17, Ctr9
초록	Background: Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic transcription factor associated with the JAK/STAT signaling pathway. In T lymphocytes, STAT3 is activated by IL-6 and TGFβ and promotes T cell survival and differentiation of T helper 17 cells; in tubular epithelial cells, STAT3 is activated by severe oxidative stress or ischemia-reperfusion (IR) injury and compromises adaptation to hypoxia. STAT3 activates its target genes by interacting with chromatin proteins and components of general transcription machinery. Cln three requiring 9 (Ctr9), a subunit of the RNA polymerase II-associated factor complex, activates or represses STAT3 action depending on cell type and disease context. Here, we investigated the role of STAT3 in promoting IR-induced renal inflammation. Methods: Mice with T cell-selective STAT3 deletion were created using Cre recombinase technique. Independently, we administered caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) for systemic inhibition of STAT3. IR injury was induced in both models, and the effect of STAT3 inhibition was assessed in comparison with their wild-type counterparts. The activation of T helper 17 cells in the ischemic kidney were evaluated by flow cytometry. The expression of Ctr9 in the kidney was determined using immunohistochemical staining and real-time PCR. To assess the effect of STAT3 and Ctr9 inhibition, primary human tubular epithelial cells were pre-treated with CADPE or Ctr9-siRNAs and grown under 1% oxygen for 6 hours. Results: Forty-eight hours after IR injury, renal dysfunction was significantly reduced in animals with T cell-selective or systemic STAT3 inhibition. This protective effect of T cell-selective STAT3 inhibition was comparable to CADPE treatment in terms of the extent of renal inflammation and the decrease in the production of pro-inflammatory cytokines. Importantly, both models of STAT3 inhibition led to a significant decrease in intrarenal CD4+ IL-17+ T cells and IL-17 expression. We observed that Ctr9 was moderately expressed in the nuclei of renal tubular epithelial cells of sham animals and that Ctr9 showed an inverse relationship with STAT3: its expression was repressed in wild-type mice with IR injury, and was partially restored with T cell-selective STAT3 deletion or CADPE treatment. Hypoxia upregulated phosphorylated STAT3, IL-17 receptor, and other markers of cell injury (e.g. IL-18) in tubular epithelial cells. Ctr9-siRNA enhanced the activation of STAT3 and the expression of other injury markers, indicating its repressive role on STAT3 action. CADPE treatment significantly, but not completely, reduced STAT3 activation and cell damage. Conclusion: Inhibition of STAT3 in T lymphocytes or tubular epithelial cells confers significant protection against renal ischemia-reperfusion injury. Ctr9 was inversely correlated with STAT3 and its inhibition further activated STAT3 and aggravated hypoxic injury.
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