Lajos Markó1,2,3,4, Joon-Keun Park5, Norbert Henke6, Song Rong5,7, András Balogh1,2,3,4, Samuel Klamer1, Hendrik Bartolomaeus1,2,3,4,8, Nicola Wilck1,2,3,4, Jürgen Ruland9,10,11, Sofia K Forslund1,2,3,4,8, Friedrich C Luft1,8, Ralf Dechend1,2,3,4,12, Dominik N Müller1,2,3,4,8. 1. Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. 2. DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany. 3. Berlin Institute of Health (BIH), Berlin, Germany. 4. Charité-Universitätsmedizin Berlin, Berlin, Germany. 5. Hannover Medical School, Hannover, Germany. 6. Helios Clinic Damp, Berlin, Germany. 7. Transplantation Center, Zunyi Medical College, Zunyi, China. 8. Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 9. Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany. 10. Center for Translational Cancer Research (TranslaTUM), Munich, Germany. 11. German Cancer Consortium (DKTK), partner Site, Munich, Germany. 12. Helios Clinic Berlin-Buch, Berlin, Germany.
Abstract
AIMS: 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. 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/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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. 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/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. CONCLUSION:Bcl10 has multi-faceted actions in Ang II-induced renal damage. On the one hand, global Bcl10deficiency 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. Published on behalf of the European Society of Cardiology. All rights reserved.