In vivo bradykinin B2 receptor activation reduces renal fibrosis

Schanstra, Joost P.; Neau, Eric; Drogoz, Pascale; Gomez, Miguel A. Arevalo; Novoa, José Miguel López; Calise, Denis; Pécher, Christiane; Bäder, Michael; Girolami, Jean-Pierre; Bascands, Jean-Loup

doi:10.1172/jci0215493

Cited by 137 publications

(68 citation statements)

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“…Similar observations have been reported in mice lacking the B2R (34). We also showed that renal fibrosis is increased in B2R null mice in response to unilateral obstruction (58). These three recent reports indicate that absence of B2R worsen DN, thereby suggesting that BK, through activation of the B2R, could exert potent nephroprotective effects.…”

Section: Discussionsupporting

confidence: 90%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

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Section: Discussionsupporting

confidence: 90%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…However, the AT2 receptor promotes apoptosis, and its absence has resulted in inadequate apoptosis and greater fibrosis (19). Thus, maintaining local AT2 receptor activation could potentially promote regression, while increased bradykinin caused by ACEI decreases renal fibrosis (20).…”

mentioning

confidence: 99%

Regression Lines in Chronic Kidney Disease

Fogo¹

2003

Journal of the American Society of Nephrology

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Chronic kidney disease (CKD) has been recognized for millennia. The great physicians Rhazes (865-925 AD) and Abu Sina (aka Avicenna, 980 -1037 AD) in ancient Persia described kidney diseases in detail. In medieval times, the pisse prophets predicted outcomes for patients on the basis of uroscopy analyses. Categorization of CKD developed in the 20 th century from the nonspecific "Bright's disease" with the advent of renal biopsy analysis. Patients could now survive with CKD with dialysis, made possible by the inventions of Kolf, Scribner, and others, or transplant. The rate of progression in individual patients could be determined by analyzing the linear regression plots of the inverse of serum creatinine versus time (1). Progress was made in slowing this relentless course of CKD by recognizing the key role of systemic BP control. The importance of intraglomerular BP control was recognized by the key studies of Brenner and colleagues (2). Currently, we aim beyond slowing the rate of progression. Is it possible to achieve regression of existing renal scarring? Are there treatments beyond BP control that could affect such goals?The interesting studies by Adamczak et al. (3) confirm in an experimental model that it is possible to remodel existing CKD. The authors extend previous observations and show that remodeling of vascular sclerosis, tubulointerstitial fibrosis, and even existing glomerulosclerosis is feasible (4,5). This was achieved by treatment with angiotensin-converting enzyme inhibitor (ACEI) at doses far beyond BP control. What could be possible mechanisms involved in this regression? Clearly, both systemic and local glomerular pressures are key in perpetuating a vicious cycle of progressive damage. Numerous additional factors have also been implicated in progressive renal scarring, including for instance reactive oxygen species, growth factors, chemokines, cytokines, proteinuria, and cell-specific injury. This plethora of pro-fibrotic mechanisms indicates that it is unlikely that any single intervention could have optimal effect on amelioration, let alone regression of progressive kidney diseases.Although new glomeruli cannot be grown after birth, glomeruli can regenerate new segments after injury, both by capillary lengthening and branching (6). Mesangial cells and glomerular endothelial cells readily proliferate after injury. In contrast, the podocyte exhibits high expression of cyclin-dependent kinase inhibitors, and normally has minimal capacity to proliferate (7). Of note, although regression was achieved by high-dose angiotensin inhibition by Adamczak et al., podocytes did not show any detectable change in number or size, perhaps reflecting this limited growth responsiveness. On the basis of our mathematical analysis, glomeruli with greater than 50% of their tuft sclerosed are not capable of regeneration of the remaining tuft (5).

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“…Consequently, all markers of fibrosis (collagen, macrophages and myofibroblasts) were improved in ko-B 1 animals relative to wt. These findings could be reproduced using a B 1 agonist, demonstrating pharmacotherapeutic potential, whereas ko-B 2 , or pharmacological B 2 antagonism in wt animals, was associated with elevated renal fibrosis, indicating that B 1 receptors aggravate while B 2 receptors protect against renal fibrosis (26,27). Other studies suggest the B 1 receptor may adversely regulate energy balance by influencing leptin signalling; B 1 receptor ko animals administered a high-fat diet showed inhibition of weight gain, improved lipid oxidation, reduced food intake and increased leptin sensitivity.…”

Section: Physiological Responsementioning

confidence: 87%

New topics in bradykinin research

Maurer

Bäder

Baş

et al. 2011

Allergy

155

129

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The kinins are a family of vasoactive peptides including bradykinin, kallidin and methionyl-lysyl-bradykinin, the latter two compounds being converted very rapidly to bradykinin by aminopeptidases. Bradykinin is a low molecular weight (1060.21 Da; C 50 H 73 N 15 O 11 ) nonapeptide, which is rapidly metabolized by endogenous metalloproteases including angiotensin-converting enzyme (ACE or kininase II), neutral endopeptidase (NEP or neprilysin), carboxypeptidase N (CPN or kininase I) and aminopeptidase P (1). Bradykinin has only a short plasma half-life of 15 s, and circulating levels are usually relatively low (0.2-7.1 pM) (2, 3).Much progress was made in understanding the physiological role of kinins with the development of selective antagonists for endothelial B 1 and B 2 receptors (4) and of C1 esterase inhibitor (C1-INH)-and B 2 -receptor-transgenic mice (5, 6). Bradykinin binds these receptors, exerting potent effects in different pathophysiological states (7) (Fig. 1). For example, bradykinin exerts potent antihypertensive, antithrombogenic, antiproliferative and antifibrogenic effects (8) as summarised in Table 1. Bradykinin also participates in inflammatory processes by activating endothelial cells to promote vasodilation and increased vascular permeability, producing classical symptoms of inflammation such as redness, heat, swelling and pain (1, 9). Specifically, bradykinin contributes to tissue hyper-responsiveness and local inflammation in allergic rhinitis, asthma and anaphylaxis, while bradykinin-dependent angioedema can result from hereditary or acquired C1-INH deficiency or the use of ACE inhibitors (ACEi) to treat hypertension, heart failure, diabetes or scleroderma. AbstractBradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B 1 and B 2 receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.

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In vivo bradykinin B2 receptor activation reduces renal fibrosis

Cited by 137 publications

References 35 publications

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Regression Lines in Chronic Kidney Disease

New topics in bradykinin research

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