A complex role for Bcl10 in kidney injury

This editorial refers to ‘B-cell lymphoma/leukemia 10 and angiotensin II-induced kidney injury’, by L. Markó et al., pp. 1059–1070.

Elevated blood pressure as a risk factor significantly contributes to cardiovascular disease and chronic kidney disease. Hypertensive nephropathy is one of the leading causes of end-stage renal disease.¹ Apart from contributing to essential hypertension, aberrant activation of the renin–angiotensin system (RAS) also exacerbates end-organ damage independently from elevations in blood pressure.²

The key effector molecule of the RAS, angiotensin II (Ang-II), can aggravate kidney damage by stimulating immune responses and inflammatory signalling cascades.² Of many downstream pathways induced by Ang-II, including MAPK, PI3K/AKT, ERK, and PKC, NF-κB signalling as a pro-inflammatory cascade significantly exacerbates kidney damage.³ Accordingly, targeting NF-κB signals by pharmacological inhibition or conditional gene targeting attenuates end-organ damage independently of blood pressure.^4,5 Studies have shown that Ang-II-dependent activation of NF-κB involves the ‘CBM’ signalosome, which is comprised of three major proteins: CARMA1/3 (Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1/3), Bcl10 (B cell lymphoma/leukaemia 10), and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1). CARMA3 is highly homologous to CARMA1 in the CBM signalosome and mainly expressed in non-immune cells, whereas CARMA1 is expressed in the immune compartment. Bcl10 is an intermediate bridging factor that cooperates with the other two proteins to form the CBM complex. CBM signalosome-mediated NF-κB activation is critical for Ang-II-dependent inflammation emanating from both immune and non-immune cells.⁶ The Müller group previously discovered that Bcl10 augments accumulation of both immune cells and non-cardiac fibroblasts in the heart with consequent cardiac damage during Ang-II-dependent hypertension. Thus, Bcl10 acts in multiple cell types to instigate Ang-II-induced cardiac damage.⁷ As the highest expression of the CARMA3 signalosome components is seen in the kidney, where Ang-II upregulates angiotensinogen via an NF-κB-dependent pathway,⁷ understanding whether Bcl10 regulates intra-renal RAS augmentation and the resulting kidney injury warrants scrutiny.⁸

Markó et al.⁹ determine the effects of Bcl10 on Ang-II-induced nephropathy. Consistent with the group’s previous data, global Bcl10-deficient (‘KO’) and wild-type (‘WT’) mice showed similar elevations in blood pressures in response to Ang-II.⁷ Despite these similar blood pressures, Ang-II-infused Bcl10 KO mice exhibited attenuations in renal immune cell infiltration and kidney fibrosis compared to WT controls. The blunted fibrosis in the KO kidneys is congruent with their previous studies investigating cardiac fibrosis. However, Bcl10 KO mice developed higher levels of albuminuria as well as more severe tubular and glomerular injury compared to Ang-II-treated WT controls. Accordingly, these data suggest that immune cell infiltration and kidney fibrosis do not always parallel tubular and glomerular damage. As the podocyte is a key component of the glomerular filtration barrier, the authors measured expression of podocyte markers in the kidney and found these to be blunted in the KO cohort, suggesting that Bcl10 protects against disruptions in podocyte architecture that permit the leakage of albumin into the urine.

To further dissect the actions of Bcl10 in the kidney vs. immune cells on renal injury, the authors transplanted kidneys between WT and Bcl10 KO animals. Renal-specific loss of Bcl10 did not modulate immune cell infiltration and renal fibrosis but markedly aggravated the levels of albuminuria, podocyte damage, and loss. Thus, Bcl10 in intrinsic kidneys cells maintains podocyte integrity and health following RAS activation. Collectively, Bcl10 has divergent actions in the various renal compartments subjected to an Ang-II-mediated insult.

Combined with their previous studies, Markó et al. provide convincing evidence that Bcl10 accentuates Ang-II-induced immune cell infiltration and fibrosis in the kidney and heart through blood pressure-independent mechanisms. On the other hand, Bcl10 protects against albuminuria and podocyte damage. At least two potential mechanisms to explain this dichotomy present themselves. First, Bcl10 has an NF-κB-independent role in F-actin cytoskeleton remodelling involved in T cell and macrophage.^10,11 However, F-actin as a component of the actin cytoskeleton maintains podocyte structure and integrity. Thus, deficiency of Bcl10 can mute immune activation while at the same time disrupting the cytoskeleton and structure of the podocyte. Second, other cells intrinsic to the glomerulus such as endothelial and mesenchymal cells may preserve podocyte phenotype and function via cytokine or growth factor-mediated crosstalk.¹² To more clearly elucidate the cell-specific actions of Bcl10 in vivo, further studies using conditional gene targeting may be required that can pinpoint the precise cell lineages through which Bcl10 regulates compartment-specific pathology in the hypertensive kidney.

In summary, the findings by Markó et al. establish that Bcl10 is a crucial component in mediating signals from immune and type 1 angiotensin (AT1) receptors to modulate NF-κB-dependent target organ damage (Figure 1). These studies advance our knowledge of Bcl10’s effects on immune cell trafficking and scar formation in the kidney and heart. On the other hand, these studies challenge the paradigm that infiltration of immune cells into a target organ during Ang-II-dependent hypertension uniformly provokes tissue damage in all compartments.¹³ In general, blocking AT1 receptor signals ameliorates hypertension-induced kidney and cardiac injury, potentially via a cascade involving AT1, CBM3, and NF-κB in mononuclear cells. Nevertheless, the divergent, cell-specific actions of Bcl-10 in multiple renal compartments demonstrate the challenges of precisely targeting Bcl10-mediated NF-κB signals for the treatment of immune, cardiac, and renal diseases.

Figure 1.

Bcl10 has divergent actions in the specific renal compartments following an Ang-II-mediated insult. The Bcl10-containing CBM signalosome mediates Ang-II-induced NF-κB activation, which is critical for inflammation emanating from both immune and non-immune cells. These cells then contribute to cardiac injury, fibrosis and arrhythmias in heart, and kidney fibrosis in the setting of Ang-II-dependent hypertension. However, Bcl10 protects against disruptions in podocyte architecture that permit the leakage of albumin into the urine and the subsequent kidney injury. Ang-II, angiotensin II; BCL10, B cell lymphoma/leukaemia 10; CARMA3, caspase recruitment domain-containing membrane-associated guanylate kinase protein 3; CBM, CARMA3-Bcl10-MALT1; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1.

Conflict of interest: none declared.

Funding

The authors acknowledge funding from NIH (DK118019 and HL128355); US Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development (BX000893); and American Heart Association (18TPA34170047).

The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.