Resolution of renal inflammation: a new role for NF-κB1 (p50) in inflammatory kidney diseases (original) (raw)
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Resolution of renal inflammation: a new role for NF- B1 (p50) in inflammatory kidney diseases
AJP: Renal Physiology, 2009
In renal tissue injury, activation of the transcription factor NF-κB has a central role in the induction of proinflammatory gene expression, which are involved in the development of progressive renal inflammatory disease. The function of NF-κB during the switch from the inflammatory process toward resolution, however, is largely unknown. Therefore, we assessed the time-dependent activation and function of NF-κB in two different models of acute nephritis. Our experiments demonstrate a biphasic activation of NF-κB in the anti-Thy-1 model of glomerulonephritis in rats and the LPS-induced nephritis in mice, with a first peak during the induction phase and a second peak during the resolution period. After induction of glomerular immune injury in rats, predominantly NF-κB p65/p50 heterodimer complexes are shifted to the nucleus whereas during the resolution phase predominantly p50 homodimers could be demonstrated in the nuclear compartment. In addition, we could demonstrate that p50 prote...
Journal of the American Society of Nephrology, 2010
The NF-B family of transcription factors regulates the induction and resolution of inflammation. Two main pathways, classical and alternative, control the nuclear translocation of NF-B. Classical NF-B activation is usually a rapid and transient response to a wide range of stimuli whose main effector is RelA/p50. The alternative NF-B pathway is a more delayed response to a smaller range of stimuli resulting in DNA binding of RelB/p52 complexes. Additional complexity in this system involves the posttranslational modification of NF-B proteins and an everincreasing range of co-activators, co-repressors, and NF-B complex proteins. Collectively, NF-B regulates the expression of numerous genes that play a key role in the inflammatory response during human and experimental kidney injury. Multiple stimuli activate NF-B through the classical pathway in somatic renal cells, and noncanonical pathway activation by TWEAK occurs in acute kidney injury. Under most test conditions, specific NF-B inhibitors tend to reduce inflammation in experimental kidney injury but not always. Although many drugs in current use clinically influence NF-B activation, there are no data regarding specific NF-B inhibition in human kidney disease.
NF-kappaB in renal inflammation
Journal of the American Society of Nephrology : JASN, 2010
The NF-kappaB family of transcription factors regulates the induction and resolution of inflammation. Two main pathways, classical and alternative, control the nuclear translocation of NF-kappaB. Classical NF-kappaB activation is usually a rapid and transient response to a wide range of stimuli whose main effector is RelA/p50. The alternative NF-kappaB pathway is a more delayed response to a smaller range of stimuli resulting in DNA binding of RelB/p52 complexes. Additional complexity in this system involves the posttranslational modification of NF-kappaB proteins and an ever-increasing range of co-activators, co-repressors, and NF-kappaB complex proteins. Collectively, NF-kappaB regulates the expression of numerous genes that play a key role in the inflammatory response during human and experimental kidney injury. Multiple stimuli activate NF-kappaB through the classical pathway in somatic renal cells, and noncanonical pathway activation by TWEAK occurs in acute kidney injury. Unde...
The NF-κB1 is a key regulator of acute but not chronic renal injury
Cell death & disease, 2017
The NF-κB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses. However, recent data has suggested that different subunits of the NF-κB family can suppress the inflammatory response. NF-κB1, from the locus nfκb1, can inhibit transcription, acting as a brake to the recognised pro-inflammatory activity of other NF-κB subunits. We tested the function of NF-κB1 in an acute (nephrotoxic serum (NTS) nephritis) and a chronic (unilateral ureteric obstruction (UUO)) model of renal injury using NF-κB1 (nfκb1(-/-)) knockout mice. Deficiency in NF-κB1 increased the severity of glomerular injury in NTS-induced nephritis and was associated with greater proteinuria and persistent pro-inflammatory gene expression. Induction of disease in bone marrow chimeric mice demonstrated that the absence of NF-κB1 in either bone marrow or glomerular cells increased the severity of injury. Early after UUO (day 3) ...
Journal of The American Society of Nephrology, 2010
The NF-B family of transcription factors regulates the induction and resolution of inflammation. Two main pathways, classical and alternative, control the nuclear translocation of NF-B. Classical NF-B activation is usually a rapid and transient response to a wide range of stimuli whose main effector is RelA/p50. The alternative NF-B pathway is a more delayed response to a smaller range of stimuli resulting in DNA binding of RelB/p52 complexes. Additional complexity in this system involves the posttranslational modification of NF-B proteins and an everincreasing range of co-activators, co-repressors, and NF-B complex proteins. Collectively, NF-B regulates the expression of numerous genes that play a key role in the inflammatory response during human and experimental kidney injury. Multiple stimuli activate NF-B through the classical pathway in somatic renal cells, and noncanonical pathway activation by TWEAK occurs in acute kidney injury. Under most test conditions, specific NF-B inhibitors tend to reduce inflammation in experimental kidney injury but not always. Although many drugs in current use clinically influence NF-B activation, there are no data regarding specific NF-B inhibition in human kidney disease.
The FASEB Journal, 2011
Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O 2). Prolonged exposure to NO/O 2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO ؎ O 2. Exposure to NO and O 2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-B activity. Cells lacking functional NF-B p65 subunit were more sensitive to NO/O 2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-B and susceptibility to the cytotoxicity of NO/O 2. Despite the reduced NF-B activity in cells exposed to NO ؎ O 2 , IB␣ was degraded, suggesting that pathways regulating the steady-state levels of IB were not involved. However, exposure to NO/O 2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-B p65 subunit. These results suggest that NO/O 2induced apoptosis occurs by suppressing NF-B activity.
Frontiers in Physiology
High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups-progressors and non-progressors-could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.
American Journal of Pathology, 2002
Nuclear factor (NF)-B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.1 rat model, gliotoxin (75 g/rat/day, 10 days, n ؍ 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 g/mouse/day, 7 days, n ؍ 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-B activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. In cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the IB␣ subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases. Supported by the Fondo de Investigaciones Sanitarias (grants FIS 99/ 0425, 00/0111), the Comunidad de Madrid (grants 08.3/0002/