Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei 11490, Taiwan.
Cells. 2021 Nov 6;10(11):3060. doi: 10.3390/cells10113060.
Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.
肾间质病变（TILs）是慢性肾脏病进展为终末期肾病的常见病理标志，其特征为肾脏进行性炎症和明显纤维化。然而，目前治疗这些病变的方法仍然效果不佳。此前，我们证明人肾组织和尿液中升高的 IL-36α 水平与肾功能受损有关，IL-36 信号增强了 TILs 小鼠模型中 NLRP3 炎性体的激活。最近，我们合成了 NSC828779，一种水杨酰苯胺衍生物（受美国专利保护，专利号为 US 8975255 B2 和 US 9162993 B2），它具有高免疫调节效力和低 IC 抑制 NF-κB 信号的激活，我们假设它将是一种治疗肾 TILs 的潜在药物候选物。本研究通过单侧输尿管梗阻（UUO）小鼠模型和相关细胞模型（包括在机械诱导的持续压力下的肾小管上皮细胞）验证了 NSC828779 对 TILs 的治疗效果。在 UUO 小鼠中，NSC828779 的治疗改善了肾脏病变，表现为肾脏炎症和纤维化的严重程度明显降低，尿细胞因子水平降低。这种小分子特异性抑制 IL-36α/NLRP3 炎性体途径。基于这些结果，有益的结果代表了对 IL-36α 激活的 MAPK/NLRP3 炎性体和 STAT3 和 Smad2/3 依赖性纤维发生信号的协同抑制。NSC828779 作为一种治疗肾脏进行性炎症和纤维化的新药候选物似乎是合理的。
