NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation
NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation
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NLRC5 缺乏通过减轻炎症来改善糖尿病肾病
DOI：
10.1096/fj.201700511rr
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发表时间：
2018-02-01
期刊：
影响因子：
4.8
通讯作者：
Peng, Wenhui
中科院分区：
文献类型：
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作者：
Luan, Peipei;Zhuang, Jianhui;Peng, Wenhui
NOD样受体家族半胱天冬酶募集结构域家族结构域5（NLRC 5）在炎症和天然免疫中具有重要作用。NLRC 5在链脲佐菌素诱导的糖尿病小鼠、db/db小鼠和糖尿病患者的肾脏中高表达。基于此，本研究旨在探讨NLRC 5在糖尿病肾病（DN）进展中的作用。我们研究了Nlrc 5基因敲除（Nlrc 5（-/-））和野生型（WT）糖尿病小鼠的肾损伤，包括炎症和纤维化。我们发现，Nlrc 5（-/-）小鼠与WT小鼠相比，糖尿病肾损伤不太严重，表现出较低的白蛋白尿，较少的纤连蛋白和IV型胶原蛋白表达，减少巨噬细胞浸润，但糖尿病肾脏中podocin和nephrin水平较高。进一步研究了高糖对体外培养的巨噬细胞和系膜细胞的作用机制。在Nlrc 5（-/-）小鼠的腹腔巨噬细胞中观察到促炎作用降低，与NF-κ B通路抑制相关。高糖条件下肾小球系膜细胞中NLRC 5的敲低也与NF-κ B和TGF-β/Smad信号转导的减少有关。总之，NLRC 5在DN进展期间部分地通过对NF-κ B和TGF-β/Smad通路的影响促进炎症和纤维化。因此，NLRC 5可能是DN治疗的一个有希望的治疗靶点。
NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5(-/-)) and wild-type (WT) diabetic mice. We found that Nlrc5(-/-) mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5(-/-) mice, associated with NF-kappa B pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-kappa B and TGF-beta/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-kappa B and TGF-beta/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.