Inflammation and Inflammatory Mediators in Kidney Disease IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats
Inflammation and Inflammatory Mediators in Kidney Disease IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats
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DOI：
10.1152/ajprenal.00462.2016
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发表时间：
2017-03-01
影响因子：
4.2
通讯作者：
Basile, David P.
中科院分区：
文献类型：
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作者：
Mehrotra, Purvi;Collett, Jason A.;Basile, David P.
T 细胞与急性肾损伤 (AKI) 及其进展为慢性肾病 (CKD) 的发病机制有关。先前的研究表明，Th17 细胞参与 AKI 向 CKD 的转变，并且霉酚酸酯 (MMF) 或氯沙坦抑制 T 细胞活性可减轻 AKI 后纤维化的发展。我们假设 T 细胞缺陷大鼠的 IL-17 细胞因子水平可能降低，从而导致 AKI 后纤维化减少。对 T 细胞缺陷型无胸腺大鼠 (Foxn1(rnu- /rnu -)) 和对照正常胸腺大鼠 (Foxn1(rnu-/+)) 进行肾缺血再灌注 (I/R)，第 33 天的单侧肾切除术和随后暴露于 4.0% 钠饮食会加速 CKD 进展。心境正常的大鼠出现肾纤维化，MMF 治疗可减轻肾纤维化。无胸腺大鼠表现出类似程度的纤维化，但这不受 MMF 治疗的影响。 FACS 分析表明，缺血后无胸腺大鼠与正常大鼠之间的 IL-17(+) 细胞数量相似。心境正常的大鼠中IL-17的产生主要来自常规T细胞（CD3(+)/CD161(-)）。在无胸腺大鼠中缺乏常规T细胞的情况下，涉及自然杀伤细胞(CD3(-)/CD161(+))的代偿途径是IL-17的主要来源。与载体处理的对照组相比，使用 IL-17Rc 受体阻断 IL-17 活性可显着减少胸腺正常和无胸腺大鼠的纤维化和中性粒细胞募集。综上所述，这些数据表明 IL-17 分泌可能通过中性粒细胞的募集参与 AKI 诱导的纤维化的发病机制，并且 IL-17 的来源可能来自常规 T 细胞或 NK 细胞。
T cells have been implicated in the pathogenesis of acute kidney injury (AKI) and its progression to chronic kidney disease (CKD). Previous studies suggest that Th17 cells participate during the AKI-to-CKD transition, and inhibition of T cell activity by mycophenolate mofetil (MMF) or losartan attenuates the development of fibrosis following AKI. We hypothesized that T cell-deficient rats may have reduced levels of IL-17 cytokine leading to decreased fibrosis following AKI. Renal ischemis-reperfusion(I/R) was performed on T cell-deficient athymic rats (Foxn1(rnu- /rnu -)) and control euthymic rats (Foxn1(rnu-/+)), and CKD progression was hastened by unilateral nephrectomy at day 33 and subsequent exposure to 4.0% sodium diet. Renal fibrosis developed in euthymic rats and was reduced by MMF treatment. Athymic rats exhibited a similar degree of fibrosis, but this was unaffected by MMF treatment. FACS analysis demonstrated that the number of IL-17(+) cells was similar between postischemic athymic vs. euthymic rats. The source of IL-17 production in euthymic rats was predominately from conventional T cells (CD3(+)/CD161(-) ). In the absence of conventional T cells in athymic rats, a compensatory pathway involving natural killer cells (CD3(-)/CD161(+)) was the primary source of IL-17. Blockade of IL-17 activity using IL-17Rc receptor significantly decreased fibrosis and neutrophil recruitment in both euthymic and athymic rats compared with vehicletreated controls. Taken together, these data suggest that IL-17 secretion participates in the pathogenesis of AKI- induced fibrosis possibly via the recruitment of neutrophils and that the source of IL-17 may be from either conventional T cells or NK cells.