B-cell lymphoma/leukemia 10 (Bcl10) and angiotensin II-induced kidney injury.

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.

[1]  T. B. Huber,et al.  The Evolving Complexity of the Podocyte Cytoskeleton. , 2017, Journal of the American Society of Nephrology : JASN.

[2]  Wei-wei Wang,et al.  The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis , 2016, Cellular Physiology and Biochemistry.

[3]  J. Becker,et al.  Live or Let Die: Is There any Cell Death in Podocytes? , 2016, Seminars in nephrology.

[4]  K. Homma,et al.  Podocyte-specific NF-κB inhibition ameliorates proteinuria in adriamycin-induced nephropathy in mice , 2016, Clinical and Experimental Nephrology.

[5]  D. Harrison,et al.  Inflammation, immunity, and hypertensive end-organ damage. , 2015, Circulation research.

[6]  P. Lucas,et al.  Bcl10 Mediates Angiotensin II–Induced Cardiac Damage and Electrical Remodeling , 2014, Hypertension.

[7]  D. Harrison,et al.  DC isoketal-modified proteins activate T cells and promote hypertension. , 2014, The Journal of clinical investigation.

[8]  L. Navar,et al.  The absence of intrarenal ACE protects against hypertension. , 2013, The Journal of clinical investigation.

[9]  F. Thaiss,et al.  Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. , 2012, American journal of physiology. Renal physiology.

[10]  J. Ruland,et al.  The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles. , 2012, Developmental cell.

[11]  F. Luft,et al.  Immune mechanisms in angiotensin II-induced target-organ damage , 2012, Annals of medicine.

[12]  P. Lucas,et al.  From MALT lymphoma to the CBM signalosome , 2011, Cell cycle.

[13]  T. Coffman,et al.  AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure. , 2011, Cell metabolism.

[14]  R. Schmieder.  End organ damage in hypertension. , 2010, Deutsches Arzteblatt international.

[15]  P. Lucas,et al.  Thrombin-dependent NF-κB Activation and Monocyte/Endothelial Adhesion Are Mediated by the CARMA3·Bcl10·MALT1 Signalosome* , 2010, The Journal of Biological Chemistry.

[16]  P. Lucas,et al.  The CARMA3-Bcl10-MALT1 Signalosome Promotes Angiotensin II-dependent Vascular Inflammation and Atherogenesis* , 2010, The Journal of Biological Chemistry.

[17]  Hyung-Suk Kim,et al.  Lymphocyte responses exacerbate angiotensin II-dependent hypertension. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[18]  J. Gutkind,et al.  CXCL8/IL8 Stimulates Vascular Endothelial Growth Factor (VEGF) Expression and the Autocrine Activation of VEGFR2 in Endothelial Cells by Activating NFκB through the CBM (Carma3/Bcl10/Malt1) Complex* , 2009, Journal of Biological Chemistry.

[19]  D. Harrison,et al.  Is hypertension an immunologic disease? , 2008, Current cardiology reports.

[20]  M. Zenke,et al.  Novel Role for Inhibitor of Differentiation 2 in the Genesis of Angiotensin II–Induced Hypertension , 2008, Circulation.

[21]  D. Harrison,et al.  Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction , 2007, The Journal of experimental medicine.

[22]  R. Dietz,et al.  Vascular Endothelial Cell–Specific NF-&kgr;B Suppression Attenuates Hypertension-Induced Renal Damage , 2007, Circulation research.

[23]  D. Krappmann,et al.  CARD-Bcl10-Malt1 Signalosomes: Missing Link to NF-κB , 2007, Science's STKE.

[24]  T. Mak,et al.  Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization1 , 2007, The Journal of Immunology.

[25]  S. Eguchi,et al.  Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. , 2007, Clinical science.

[26]  T. Mak,et al.  CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells , 2007, Proceedings of the National Academy of Sciences.

[27]  Phillip Ruiz,et al.  Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney , 2006, Proceedings of the National Academy of Sciences.

[28]  T. Gilmore.  Introduction to NF-κB: players, pathways, perspectives , 2006, Oncogene.

[29]  A. Kribben,et al.  CCL19-IgG prevents allograft rejection by impairment of immune cell trafficking. , 2006, Journal of the American Society of Nephrology : JASN.

[30]  J. Egido,et al.  Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[31]  N. Gretz,et al.  Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. , 2004, Journal of the American Society of Nephrology : JASN.

[32]  Matthias Kretzler,et al.  Cell biology of the glomerular podocyte. , 2003, Physiological reviews.

[33]  F. Luft,et al.  Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage , 2002, Hypertension.

[34]  M. Zenke,et al.  Immunosuppressive treatment protects against angiotensin II-induced renal damage. , 2002, The American journal of pathology.

[35]  David Baltimore,et al.  CARD11 mediates factor‐specific activation of NF‐κB by the T cell receptor complex , 2002, The EMBO journal.

[36]  G. Viberti,et al.  Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus: A Blood Pressure–Independent Effect , 2002, Circulation.

[37]  J. Tschopp,et al.  CARMA1 is a critical lipid raft–associated regulator of TCR-induced NF-κB activation , 2002, Nature Immunology.

[38]  J. Bertin,et al.  A requirement for CARMA1 in TCR-induced NF-κB activation , 2002, Nature Immunology.

[39]  F. Thaiss,et al.  Angiotensin II activates nuclear transcription factor-κB through AT1 and AT2 receptors11See Editorial by Luft, p. 2272. , 2002 .

[40]  F. Thaiss,et al.  Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. , 2002, Kidney international.

[41]  T. Sugaya,et al.  Angiotensin III activates nuclear transcription factor-kappaB in cultured mesangial cells mainly via AT(2) receptors: studies with AT(1) receptor-knockout mice. , 2002, Journal of the American Society of Nephrology : JASN.

[42]  M. Nieminen,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[43]  D. Harrison,et al.  The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis. , 2002, Circulation.

[44]  J. Egido,et al.  Angiotensin II and renal fibrosis. , 2001, Hypertension.

[45]  Yusuke Suzuki,et al.  Proinflammatory actions of angiotensins , 2001, Current opinion in nephrology and hypertension.

[46]  T. Mak,et al.  Bcl10 Is a Positive Regulator of Antigen Receptor–Induced Activation of NF-κ B and Neural Tube Closure , 2001, Cell.

[47]  Bruce H. R. Wolffenbuttel,et al.  Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy , 2000, The Lancet.

[48]  D. Ganten,et al.  NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats , 2000 .

[49]  D. Ganten,et al.  Hypertension-induced end-organ damage : A new transgenic approach to an old problem. , 1999, Hypertension.

[50]  L. Raij,et al.  Angiotensin II, nitric oxide, and end-organ damage in hypertension. , 1998, Kidney international. Supplement.

[51]  E. Fleck,et al.  Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin. , 1997, Circulation research.