B-cell lymphoma/leukemia 10 and angiotensin II-induced kidney injury

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Item Type:	Article
Title:	B-cell lymphoma/leukemia 10 and angiotensin II-induced kidney injury
Creators Name:	Markó, L., Park, J.K., Henke, N., Rong, S., Balogh, A., Klamer, S., Bartolomaeus, H., Wilck, N., Ruland, J., Forslund, S.K., Luft, F.C., Dechend, R. and Müller, D.N.
Abstract:	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.
Keywords:	Angiotensin II, Bcl10, Kidney, Podocyte, Albuminuria, Animals, Mice
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Oxford University Press
Volume:	116
Number:	5
Page Range:	1059-1070
Date:	1 April 2020
Official Publication:	https://doi.org/10.1093/cvr/cvz169
PubMed:	View item in PubMed

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