Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.
Cardiovasc Res. 2020 Apr 1;116(5):1059-1070. doi: 10.1093/cvr/cvz169.
B-cell lymphoma/leukaemia 10 (Bcl10) is a member of the CARMA-Bcl10-MALT1 signalosome, linking angiotensin (Ang) II, and antigen-dependent immune-cell activation to nuclear factor kappa-B signalling. We showed earlier that Bcl10 plays a role in Ang II-induced cardiac fibrosis and remodelling, independent of blood pressure. We now investigated the role of Bcl10 in Ang II-induced renal damage.
Bcl10 knockout mice (Bcl10 KO) and wild-type (WT) controls were given 1% NaCl in the drinking water and Ang II (1.44 mg/kg/day) for 14 days. Additionally, Bcl10 KO or WT kidneys were transplanted onto WT mice that were challenged by the same protocol for 7 days. Kidneys of Ang II-treated Bcl10 KO mice developed less fibrosis and showed fewer infiltrating cells. Nevertheless, neutrophil gelatinase-associated lipocalin (Ngal) and kidney injury molecule (Kim)1 expression was higher in the kidneys of Ang II-treated Bcl10 KO mice, indicating exacerbated tubular damage. Furthermore, albuminuria was significantly higher in Ang II-treated Bcl10 KO mice accompanied by reduced glomerular nephrin expression and podocyte number. Ang II-treated WT mice transplanted with Bcl10 KO kidney showed more albuminuria and renal Ngal, compared to WT- > WT kidney-transplanted mice, as well as lower podocyte number but similar fibrosis and cell infiltration. Interestingly, mice lacking Bcl10 in the kidney exhibited less Ang II-induced cardiac hypertrophy than controls.
Bcl10 has multi-faceted actions in Ang II-induced renal damage. On the one hand, global Bcl10 deficiency ameliorates renal fibrosis and cell infiltration; on the other hand, lack of renal Bcl10 aggravates albuminuria and podocyte damage. These data suggest that Bcl10 maintains podocyte integrity and renal function.
B 细胞淋巴瘤/白血病 10（Bcl10）是 CARMA-Bcl10-MALT1 信号体的成员，将血管紧张素（Ang）II 和抗原依赖性免疫细胞激活与核因子 kappa-B 信号联系起来。我们之前表明，Bcl10 在血管紧张素 II 诱导的心脏纤维化和重塑中发挥作用，与血压无关。我们现在研究了 Bcl10 在血管紧张素 II 诱导的肾脏损伤中的作用。
Bcl10 敲除小鼠（Bcl10 KO）和野生型（WT）对照给予饮用水中的 1%NaCl 和血管紧张素 II（1.44mg/kg/天）14 天。此外，将 Bcl10 KO 或 WT 肾脏移植到接受相同方案 7 天挑战的 WT 小鼠中。血管紧张素 II 处理的 Bcl10 KO 小鼠的肾脏纤维化程度较低，浸润细胞较少。然而，血管紧张素 II 处理的 Bcl10 KO 小鼠的肾脏中中性粒细胞明胶酶相关脂质运载蛋白（Ngal）和肾损伤分子 1（Kim）1 的表达更高，表明肾小管损伤加重。此外，血管紧张素 II 处理的 Bcl10 KO 小鼠的蛋白尿显著增加，同时肾小球足细胞蛋白表达降低，足细胞数量减少。与 WT- > WT 肾脏移植小鼠相比，接受血管紧张素 II 处理的 WT 小鼠移植 Bcl10 KO 肾脏后表现出更高的蛋白尿和肾脏 Ngal，以及更低的足细胞数量，但纤维化和细胞浸润相似。有趣的是，与对照相比，肾脏缺乏 Bcl10 的小鼠表现出较少的血管紧张素 II 诱导的心脏肥大。
Bcl10 在血管紧张素 II 诱导的肾脏损伤中具有多方面的作用。一方面，Bcl10 缺失可改善肾脏纤维化和细胞浸润；另一方面，肾脏缺乏 Bcl10 会加重蛋白尿和足细胞损伤。这些数据表明 Bcl10 维持足细胞完整性和肾功能。
