Abstract 038: The Dual Role of B-Cell Lymphoma/Leukemia 10 in Angiotensin II-Induced Renal Damage

Abstract

Angiotensin (Ang) II activates NF-κB and thereby induces organ damage. B-cell Lymphoma/Leukemia 10 (Bcl10) is a member of the CARMA-Bcl10-MALT1 signalosome that links Ang II and antigen-dependent activation of immune cells to NF-κB signaling. We have shown earlier that Bcl10 plays a significant role in the generation of Ang II–induced cardiac fibrosis and electric remodeling in a blood pressure independent fashion. In our present study we 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/d) for 14 days. Additionally, Bcl10 KO or WT kidneys were transplanted onto WT mice and were challenged by the same protocol for 7 days. Kidneys of Bcl10 KO mice developed less fibrosis and showed reduced number of infiltrating macrophages and T cells. Nevertheless, renal expression of neutrophil gelatinase-associated lipocalin (Ngal) and kidney injury molecule 1 expression was higher after Ang II treatment in Bcl10 KO mice compared to WT mice indicating exacerbated tubular damage (4.94±1.56 vs 1.44±0.44 and 1.14±0.22 vs 2.87±1.05 AU respectively). In addition, albuminuria was significantly higher in Ang II-treated Bcl10 KO mice than in controls (1194±238 vs. 377±112 μg/day) accompanied by reduced glomerular nephrin expression and reduced podocyte number (5.9±0.4 vs. 8.2±0.5 Wilms’ tumor-1 protein (WT1) positive cells/glomerulus). Ang II-treated WT mice transplanted with Bcl10 KO kidney showed significantly higher albuminuria (6003±1988 vs. 1779±831 μg/day) and renal Ngal expression (1.75±4.08 vs 0.71±0.57 AU) compared to WT->WT kidney transplanted mice, as well as lower podocyte number (5.4±0.3 vs. 4.9±0.2 WT1 positive cells/glomerulus) but similar extent of fibrosis and cell infiltration. Lacking Bcl10 in the kidney only was protective from Ang II-induced cardiac hypertrophy. Bcl10 has a multi-faceted action in hypertensive renal damage. While global Bcl10 deficiency ameliorates renal fibrosis and cell infiltration, the lack of renal Bcl10 aggravates albuminuria and podocyte damage. These data indicate that Bcl10 plays a crucial role in maintaining podocyte integrity and renal function.