Hepatocyte Growth Factor Exerts Its Anti-Inflammatory Action by Disrupting Nuclear Factor-κB Signaling

Giannopoulou, Myrto; Dai, Chunsun; Tan, Xiaoyue; Wen, Xiang; Michalopoulos, George K.; Liu, Youhua

doi:10.2353/ajpath.2008.070583

Cited by 113 publications

(96 citation statements)

References 58 publications

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“…In addition, HGF reduces allergic airway inflammation [42]. Anti-inflammatory action of HGF has been suggested to be mediated by phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3b and disrupting nuclear factor-kB signalling [43]. In the present study, co-administration of the neutralising anti-HGF antibody reversed the anti-inflammatory effect mediated by apoptotic Jurkat cell instillation, whereas control IgG was ineffective.…”

Section: Discussionmentioning

confidence: 50%

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Lee

Moon²,

Lee³

et al. 2012

Eur Respir J

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Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury.We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed.At 2 h after apoptotic cell instillation into bleomycin-stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced proinflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These antiinflammatory and antiapoptotic effects could be reversed by co-administration of HGFneutralising antibody.These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis.

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Section: Discussionmentioning

confidence: 50%

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Lee

Moon²,

Lee³

et al. 2012

Eur Respir J

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“…In addition, vitamin D is shown to induce the expression of hepatocyte growth factor, 40 a cytokine that has potent anti-inflammatory and antifibrotic properties. [41][42][43] In summary, we have shown in this study that paricalcitol attenuates renal infiltration of inflammatory cells and inhibits tubular RANTES expression in obstructive nephropathy. This anti-inflammatory effect of paricalcitol seems to be mediated by its ability to induce the VDR-mediated sequestration of NF-B signaling; therefore, in addition to preserving tubular epithelial integrity by blocking EMT, as previously reported, 10 active vitamin D also exerts its beneficial activities in CKD by inhibiting renal inflammation through directly disrupting NF-B signaling.…”

Section: Discussionmentioning

confidence: 97%

Paricalcitol Inhibits Renal Inflammation by Promoting Vitamin D Receptor–Mediated Sequestration of NF-κB Signaling

Tan

Wen

Liu

2008

Journal of the American Society of Nephrology

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243

194

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Inflammation is a pathologic feature of a variety of chronic kidney diseases. Several lines of evidence suggest a potential anti-inflammatory role for vitamin D in chronic kidney disease, but the underlying mechanism remains unknown. Here, the effect of the synthetic vitamin D analogue paricalcitol on renal inflammation was investigated in a mouse model of obstructive nephropathy. Paricalcitol reduced infiltration of T cells and macrophages in the obstructed kidney. This inhibition of inflammatory cell infiltration was accompanied by a decreased expression of RANTES and TNF-␣. Induction of RANTES was localized primarily to the tubular epithelium, underscoring a role for tubular cells in renal inflammation. In a human proximal tubular cell line (HKC-8), paricalcitol inhibited RANTES mRNA and protein expression and abolished the ability of tubular cells to recruit lymphocytes and monocytes after TNF-␣ stimulation. Although RANTES induction depended on NF-B signaling, paricalcitol affected neither TNF-␣-mediated IB␣ phosphorylation and degradation nor p65 NF-B activation and nuclear translocation. Instead, chromatin immunoprecipitation assay showed that paricalcitol abolished the binding of p65 to its cognate cis-acting element in the RANTES promoter. The vitamin D receptor (VDR) and p65 formed a complex in tubular cells after paricalcitol treatment, which inhibited the ability of p65 to trans-activate gene transcription. In vivo, paricalcitol did not block NF-B nuclear translocation after obstructive injury but did increase the expression and nuclear distribution of VDR. These results suggest that paricalcitol inhibits renal inflammatory infiltration and RANTES expression by promoting VDRmediated sequestration of NF-B signaling.

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“…On the other hand, administration of HGF therapy in the stenotic kidney reduced the expression of NF-B, suggesting a decrease in proinflammatory activity. Previous studies showed that anti-inflammatory actions of HGF are partly mediated by disruption of NF-B signaling (19,21). However, HGF therapy did not reduce the expression of MCP-1 and TNF-␣ in the stenotic kidney, which may explain the persistence of some inflammatory infiltrates in the HGF-treated kidneys.…”

Section: F630mentioning

confidence: 71%

Renoprotective effects of hepatocyte growth factor in the stenotic kidney

Stewart

Chade

2013

American Journal of Physiology-Renal Physiology

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Stewart N, Chade AR. Renoprotective effects of hepatocyte growth factor in the stenotic kidney. Am J Physiol Renal Physiol 304: F625-F633, 2013. First published December 26, 2012 doi:10.1152/ajprenal.00504.2012 damage and loss contribute to the progression of renal injury in renal artery stenosis (RAS). Hepatocyte growth factor (HGF) is a powerful angiogenic and antifibrotic cytokine that we showed to be decreased in the stenotic kidney. We hypothesized that renal HGF therapy will improve renal function mainly by protecting the renal microcirculation. Unilateral RAS was induced in 15 pigs. Six weeks later, single-kidney RBF and GFR were quantified in vivo using multidetector computed tomography (CT). Then, intrarenal rh-HGF or vehicle was randomly administered into the stenotic kidney (RAS, n ϭ 8; RASϩHGF, n ϭ 7). Pigs were observed for 4 additional weeks before CT studies were repeated. Renal MV density was quantified by 3D micro-CT ex vivo and histology, and expression of angiogenic and inflammatory factors, apoptosis, and fibrosis was determined. HGF therapy improved RBF and GFR compared with vehicle-treated pigs. This was accompanied by improved renal expression of angiogenic cytokines (VEGF, p-Akt) and tissue-healing promoters (SDF-1, CXCR4, MMP-9), reduced MV remodeling, apoptosis, and fibrosis, and attenuated renal inflammation. However, HGF therapy did not improve renal MV density, which was similarly reduced in RAS and RASϩHGF compared with controls. Using a clinically relevant animal model of RAS, we showed novel therapeutic effects of a targeted renal intervention. Our results show distinct actions on the existing renal microcirculation and promising renoprotective effects of HGF therapy in RAS. Furthermore, these effects imply plasticity of the stenotic kidney to recuperate its function and underscore the importance of MV integrity in the progression of renal injury in RAS. kidney; HGF; renal artery stenosis; microcirculation; remodeling; imaging MICROVASCULAR (MV) dysfunction, damage, and/or rarefaction are often observed in target organs during the progression of hypertension, diabetes, and cardiovascular disease. In turn, evidence supports a central pathophysiological role for MV dysfunction and damage in promoting cardiovascular diseaseinduced organ injury (29), underscoring a cause-effect relationship between MV disease and the pathophysiology of organ damage. In the kidney, glomerular and peritubular MV damage and loss have been linked to renal functional impairment and progression of renal damage in chronic renal disease (irrespective of the etiology) (17) and renal graft function (41). Indeed, renal MV disease is an important contributor to the progression of renal injury (23,40) and an important determinant of whether treatments are effective (7).Almost 15% of patients with renal artery stenosis (RAS) develop intractable hypertension or progressive loss of kidney function (15). RAS is the main cause of chronic renovascular disease (RVD), a disorder capable of inducing severe, progressive, a...

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Hepatocyte Growth Factor Exerts Its Anti-Inflammatory Action by Disrupting Nuclear Factor-κB Signaling

Cited by 113 publications

References 58 publications

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Paricalcitol Inhibits Renal Inflammation by Promoting Vitamin D Receptor–Mediated Sequestration of NF-κB Signaling

Renoprotective effects of hepatocyte growth factor in the stenotic kidney

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