Deletion of bradykinin B1 receptor reduces renal fibrosis

Wang, Pamella Huey Mei; Cenedeze, Marcos Antônio; Campanholle, Gabriela; Malheiros, Denise Maria Avancini Costa; Torres, Hugo Arruda de Moura; Pesquero, João Bosco; Pacheco-Silva, Álvaro; Câmara, Niels Olsen Saraiva

doi:10.1016/j.intimp.2008.10.018

Cited by 32 publications

(30 citation statements)

References 53 publications

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“…This has drawn attention to the B1R as a new therapeutic target for the treatment of pathologies related to chronic inflammation, such as airway inflammation, diabetic neuropathy, arthritis, and chronic and neuropathic pain. 15 We and others previously described that B1R blockade can reduce the development of inflammation and subsequent fibrosis in the UUO model 21,25 ; however, it remained unknown whether blockade of the B1R can inhibit immune nephropathies.…”

Section: Discussionmentioning

confidence: 99%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, HenochSchö nlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis. Rapidly progressive glomerulonephritides constitute a group of kidney diseases sharing common pathologic features. These nephropathies are characterized by severe glomerular inflammation, mainly composed of infiltrating macrophages and T cells. This leads to the formation of glomerular crescents composed of immune and proliferating epithelial cells from the Bowman's capsule. After the primary glomerular insult, inflammation and lesions extend to the tubulointerstitial compartment and induce tubular damage and progressive interstitial fibrosis, leading to the loss of renal function; therefore, renal inflammation is a key player in the initiation and the progression of these pathologies. It has been suggested that any strategy or agent able to limit or attenuate renal inflammation should significantly slow the progression of glomerulonephritides to ESRD. 1 Endogenous kinins (bradykinin-related peptides)are produced through cleavage of kininogens by kallikreins. These peptides mediate their biologic effects by activation of two G protein-coupled receptors: a constitutively expressed B2 receptor (B2R) and an inducible B1 receptor (B1R). 2 Bradykinin and kallidin are the natural agonists of the B2R, whereas their metabolites, generated by the enzyme kininase I, desArg9-BK and Lys-des-Arg9-BK, respectively, are spe-

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Section: Discussionmentioning

confidence: 99%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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“…It is important to emphasize that these changes are clearly different from the compensatory changes that occur after reduction of renal mass (42). To study renal fibrosis, induced models (surgical and chemical), spontaneous models, genetic models and in vitro models (29,(43)(44)(45)(46)(47)(48) can be used.…”

Section: Animal Models Of Renal Fibrosismentioning

confidence: 99%

“…After complete UUO in the obstructed kidney, there is a progressive decline in renal blood flow, glomerular filtration rate and rapid damage of the renal parenchyma. Most of the renal cellular alterations occur after 2-3 weeks (17), namely an increase in intratubular pressure, and consequently an extension of the tubule walls (31), epithelial tubular cell damage (72) and subsequently a significant increase in renal fibrosis indicators as inflammation mediated by macrophages (44,74) and myofibroblasts (72). These cells produce cytokines and growth factors that trigger an inflammatory process in the kidney after UUO, inducing ECM deposition and cell apoptosis.…”

Section: Unilateral Ureteral Obstructionmentioning

confidence: 99%

“…On the other hand, a combination of TGFβ antibody with angiotensin-converting enzyme inhibitors offers superior nephroprotective effects than single treatments in that it normalizes blood pressure, proteinuria and led to regression of glomerulosclerosis and tubular injuries in rats (20). Blockade of the kinin B1 receptor is another promising antifibrotic therapy for renal fibrosis in animal models of obstructive nephropathy (44,74). In another study, it was verified that the therapeutic combination of mycophenolate mofetil (immunosuppressive agent) and benazapril (angiotensin-converting enzyme inhibitor) was more effective in the treatment of renal fibrosis than mycophenolate mofetil and benazapril alone in 5/6 nephrectomized rats (9).…”

Section: Effective Treatments and New Perspectives Of Researchmentioning

confidence: 99%

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Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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Abstract. Chronic kidney disease (CKD) is a long-term condition in which theChronic kidney disease (CKD) represents a serious hazard to human health, and has a high prevalence. In developed countries, it is estimated that more than 10% of adults present some degree of CKD (1). Despite a varied initial evolution, which is related to the diversity of its aetiologies -namely genetics, autoimmune-related infections, environmental factors, diet, and drugs -progressive renal disease frequently results in renal fibrosis and finally in renal failure. The mechanisms implicated in renal fibrosis are still poorly understood, and existing therapies are ineffective or only slightly successful, hence it is essential to understand the pathophysiological mechanisms underlying the usual development of CKD, and to discover and better understand new strategies for treating this disease. In order to study the biopathology of this disease and to evaluate new treatments, animal models are required. The perfect animal model for renal disease research should have human-like renal anatomy, haemodynamics and physiology, as well as enabling the determination of relevant renal, biochemical and haemodynamic parameters. In all probability, no species can consistently meet all these requirements, and the experimental plan and other constraints often determine the choice of animal models for particular research applications. With this in mind, this review aims to describe and analyze animal models of renal fibrosis and suggest new areas of research. Renal Fibrosis: Aetiology and PathophysiologyDiabetes and hypertension are currently the two principal causes of CKD (2), among other causes such as infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations, autoimmune diseases (1) and drugs (3, 4). In general, diabetes causes glomerular hypertension by reducing the afferent arteriolar resistance while stimulating the efferent arterioles (2). Thus, elevated glomerular capillary pressure is one of the major factors in progressive renal sclerosis (5). Diabetes and hypertension gradually lead to glomerular expansion, which causes endothelial dysfunction and haemodynamic changes: loss of the glomerular basement membrane electric charge and its thickening, a decreased number of podocytes, foot-process effacement and mesangial distension have been shown to 1

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“…It is now clear that the initial events of chronic renal diseases are inflammatory response [1]. In a widely used renal injury animal model of ureteral obstruction, significant increases in monocyte chemotactic protein 1 (MCP-1), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were observed at day 3 after surgery [2][3][4]. In recent years, it has become increasingly clear that renal tubular epithelial cells, which plays an important role in tubulointerstitial inflammation, a hallmark of most renal diseases, are able to express a large variety of chemokines, cytokines/growth factors, and adhesion molecules.…”

Section: Introductionmentioning

confidence: 99%

Vasoactive Intestinal Peptide Enhances TNF-α-Induced IL-6 and IL-8 Synthesis in Human Proximal Renal Tubular Epithelial Cells by NF-κB-Dependent Mechanism

et al. 2011

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Vasoactive intestinal polypeptide (VIP) is a 28-amino acid neuropeptide with vasodilator, bronchodilator, and anti-inflammatory effects. But little is known about its pro-inflammatory effects. We investigated the effect of VIP on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), two pro-inflammatory cytokines, in TNF-α-activated proximal renal tubular epithelial cell line (HK-2 cells). Cultured HK-2 cells were treated with TNF-α in the presence or absence of VIP with a dose range from 1 to 100 nM, followed by analysis of pro-inflammatory cytokines (IL-6 and IL-8) induction and their signal events including activation of the NF-κB pathway. We report here that tumor necrosis factor-α (TNF-α) increased IL-6 and IL-8 production, and that these effects were potentiated by VIP at 10 nM in HK-2 cells. However, VIP at 1 and 100 nM did not display this function. Consistent with these observations, we were able to show that VIP at 10 nM upregulated TNF-α-induced phosphorylation of IκB-α, leading to IκB-α degradation and the subsequent nuclear translocation of NF-κB. Furthermore, VIP-enhanced activation of NF-κB transcription activity was demonstrated using a NF-κB reporter construct upon transient transfection into HK-2 cells. These results strongly suggest that VIP synergistically enhances TNF-α-stimulated IL-6 and IL-8 synthesis via activating the NF-κB pathway in HK-2 cells.

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Deletion of bradykinin B1 receptor reduces renal fibrosis

Cited by 32 publications

References 53 publications

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Vasoactive Intestinal Peptide Enhances TNF-α-Induced IL-6 and IL-8 Synthesis in Human Proximal Renal Tubular Epithelial Cells by NF-κB-Dependent Mechanism

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