Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Biosci Rep. 2018 Jul 12;38(4). doi: 10.1042/BSR20180762. Print 2018 Aug 31.
Protein overload of proximal tubular cells (PTCs) can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin nephropathy (ADR). Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg, iv), being followed for 2, 4, or 20 weeks. Massive albuminuria was associated with early activation of both the NF-κB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis, and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of Toll-like receptor (TLR) 4 (TLR4), NLRP3, MCP-1, IL6, IL-1β, Caspase-1, α-actin, and collagen-1. Silencing of and/or mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavy proteinuric disease. Inhibition of specific components of innate and/or adaptive immunity may be the basis for future strategies to prevent chronic kidney disease (CKD) in this setting.
近端肾小管细胞（PTC）的蛋白过载可通过尚不清楚的机制促进间质损伤，这些机制可能涉及固有免疫的激活。我们研究了长期暴露于高浓度蛋白的肾小管细胞是否会刺激固有免疫，从而引发进行性间质炎症和肾损伤，以及固有免疫或适应性免疫的特异性抑制是否会在阿霉素肾病（ADR）这一大量蛋白尿的既定模型中提供肾保护。雄性成年慕尼黑-维斯塔大鼠接受单次阿霉素（5mg/kg，iv）注射，然后随访 2、4 或 20 周。大量白蛋白尿与 NF-κB 和 NLRP3 固有免疫途径的早期激活有关，其强度与淋巴细胞浸润密度密切相关。此外，ADR 大鼠表现出明显的肾脏氧化应激迹象。ADR 给药 20 周后，观察到明显的间质纤维化、肾小球硬化和肾功能丧失。给予霉酚酸酯（MMF），10mg/kg/天，可预防固有免疫和适应性免疫的激活以及肾脏氧化应激和纤维化。此外，MMF 治疗与 M 从 M1 向 M2 表型的转变有关。在培养的 NRK52-E 细胞中，过量白蛋白增加了 Toll 样受体（TLR）4（TLR4）、NLRP3、MCP-1、IL6、IL-1β、Caspase-1、α-肌动蛋白和胶原-1 的蛋白含量。和/或 mRNA 的沉默消除了这种促炎/促纤维化行为。固有免疫和适应性免疫的同时激活可能是导致大量蛋白尿疾病肾损伤的关键。固有免疫和/或适应性免疫的特定成分的抑制可能是预防该环境下慢性肾病（CKD）的未来策略的基础。
