Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Mediators Inflamm. 2018 Oct 14;2018:5103672. doi: 10.1155/2018/5103672. eCollection 2018.
Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice ( ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases.
慢性炎症在大多数纤维化疾病的发生和进展中起着重要作用，但目前尚无有效的治疗方法。肾小管间质纤维化（TF）的特征是慢性肾脏病中纤维组织的不可逆转沉积。长期的损伤刺激和慢性炎症调节下游事件，导致 TF。近年来，白细胞介素-17（IL-17）与器官纤维化密切相关。然而，IL-17 受体信号在 TF 中的作用是一个活跃的争论领域。使用单侧输尿管梗阻（UUO）TF 小鼠模型，我们表明 IL-17 受体 A 缺陷小鼠（）在梗阻肾脏中表现出增加的 TF。因此，IL-17 的过表达恢复了 UUO 小鼠的保护作用。肾脏中基质降解酶的表达减少导致 ECM 蛋白无法降解，从而导致 小鼠中 TF 表型的夸大。我们证明了激肽释放酶-激肽系统（KKS）以 IL-17 依赖的方式在梗阻肾脏中被激活。因此，接受激肽释放酶激活的主要终产物缓激肽的 小鼠通过上调基质降解酶的表达来预防 TF 的发生。最后，我们表明，特异性激肽受体 1 或 2 的激动剂治疗可防止 TF 引起的肾脏损伤。总的来说，我们的结果强调了 IL-17 和 KKS 激活在 TF 保护中的重要联系，这是导致毁灭性终末期肾病的慢性肾脏疾病的共同最终结果。
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