AIMS B-cell lymphoma/leukemia 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 (NF-κB) signaling. We showed earlier that Bcl10 plays a role in Ang II-induced cardiac fibrosis and remodeling, independent of blood pressure. We now investigated the role of Bcl10 in Ang II-induced renal damage. METHODS AND RESULTS 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/d) 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. CONCLUSIONS 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. TRANSLATIONAL PERSPECTIVES The CARMA-Bcl10-MALT1 signalosome plays a pivotal role in several cell types regulating different (patho)physiological processes. For example, it links Ang II and NF-κB signaling pathways. The molecular mechanism of albuminuria upon Ang II-induced hypertension is not fully understood. Podocytes are a direct target of Ang II. We provide data that the lack of Bcl10 protects the kidney and the heart from Ang II-induced fibrosis and immune cell infiltration. Nevertheless, it aggravates albuminuria and podocyte damage independently from blood pressure. Therefore, a cell type-specific interpretation of major signaling pathway helps to better understand the pathogenesis of target organ damage.

中文翻译：

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B细胞淋巴瘤/白血病10（Bcl10）和血管紧张素II诱导的肾损伤。

AIMS 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（NF-κB）信号传导联系起来。我们较早地表明，Bcl10在Ang II诱导的心脏纤维化和重塑中起着作用，与血压无关。我们现在研究了Bcl10在Ang II诱导的肾损伤中的作用。方法和结果给Bcl10基因敲除小鼠（Bcl10 KO）和野生型（WT）对照者分别在饮用水中添加1％NaCl和Ang II（1.44 mg / kg / d），持续14天。此外，将Bcl10 KO或WT肾脏移植到受相同实验方案攻击7天的WT小鼠上。Ang II治疗的Bcl10 KO小鼠的肾脏出现较少的纤维化，并显示较少的浸润细胞。不过，中性粒细胞明胶酶相关的脂蛋白（Ngal）和肾损伤分子（Kim）1在Ang II治疗的Bcl10 KO小鼠的肾脏中表达更高，表明肾小管损害加剧。此外，在接受Ang II治疗的Bcl10 KO小鼠中，白蛋白尿明显更高，并伴有肾小球肾素表达和足细胞数量减少。与WT-> WT肾脏移植的小鼠相比，Ang II处理的Bcl10 KO肾脏移植的WT小鼠显示出更多的蛋白尿和肾脏Ngal，足细胞数量减少，但纤维化和细胞浸润相似。有趣的是，肾脏中缺乏Bcl10的小鼠表现出比对照组少的Ang II诱导的心脏肥大。结论Bcl10在Ang II引起的肾损伤中具有多方面的作用。一方面，全球性Bcl10缺乏症改善了肾纤维化和细胞浸润。另一方面，肾Bcl10缺乏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。翻译前景CARMA-Bcl10-MALT1信号小体在调节不同（病理）生理过程的几种细胞类型中起着关键作用。例如，它连接Ang II和NF-κB信号通路。蛋白尿对Ang II诱导的高血压的分子机制尚未完全了解。足细胞是Ang II的直接靶标。我们提供的数据表明，缺乏Bcl10可以保护肾脏和心脏免受Ang II诱导的纤维化和免疫细胞浸润。然而，它独立于血压加重了蛋白尿和足细胞损伤。因此，