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/jci200215493

Cited by 36 publications

(27 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, in BK B 2 receptor gene knockout mice, disruption of the BK B 2 receptor led to hypertension, LV remodelling and functional impairment [70]. The protective, antimitogenic effect of BK on ventricular remodelling processes was associated with a BK B 2 receptor-mediated increase in tPA and matrix metalloproteinase 2 (MMP2) activity [71].…”

Section: Ventricular Remodellingmentioning

confidence: 99%

The therapeutic potential of bradykinin B2 receptor agonists in the treatment of cardiovascular disease

Heitsch¹

2003

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

The nonapeptide bradykinin (BK) is a Janus-faced hormone, which exerts pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of BK B(2) receptors. In various animal models and in humans it has been shown that the stimulation of BK B(2) receptors is not only implicated in the pathogenesis of inflammation, pain and tissue injury but also in powerful cardioprotective mechanisms. Either exogenous administration of BK or locally increased BK concentrations as a consequence of the inhibition of its metabolic breakdown by angiotensin-converting enzyme inhibitors, reveal the significant contribution of BK in powerful cardioprotective mechanisms. These are mainly triggered by the synthesis and release of the vasorelaxant, anti-hypertrophic and anti-atherosclerotic endothelial mediators nitric oxide, prostaglandins and tissue-type plasminogen activator, by ischaemic preconditioning and by an increase in insulin sensitivity. Consequently, BK B(2) receptor agonists may have important clinical value in the treatment and prevention of various cardiovascular disorders such as hypertension, ischaemic heart disease, left ventricular hypertrophy, ventricular remodelling and congestive heart failure as well as diabetic disorders by mimicking the reported beneficial effects of BK. However, none of the currently known potent and selective peptide and non-peptide agonists of BK B(2) receptors--RMP-7 (lobradamil, Cereport; Alkermes), JMV-1116 (Fournier), FR-190997 (Fujisawa) and FR-191413 (Fujisawa)--have been selected for a clinical assessment in cardiovascular indications. One major challenge of this approach is the still unanswered question of whether there is a sufficient safe therapeutic window between potential cardioprotective and pro-inflammatory effects following BK B(2) receptor agonism.

show abstract

Section: Ventricular Remodellingmentioning

confidence: 99%

The therapeutic potential of bradykinin B2 receptor agonists in the treatment of cardiovascular disease

Heitsch¹

2003

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

show abstract

“…Reduced bioavailability of NO is a cornerstone of the developing endothelial dysfunction. It is instructive that therapeutic strategies proposed and used to halt the progression of nephrosclerosis, such as angiotensin-converting enzyme inhibition, activation of bradykinin B 2 receptor, L-arginine supplementation, and combinations of lisinopril and L-arginine (50,53,59), are in fact agonists of eNOS. Indeed, eNOS function appears to be a good predictor of individual susceptibility to renal damage in subtotally nephrectomized rats; it also protects Wistar Furth rats from chronic renal injury (14,21).…”

mentioning

confidence: 99%

Chronic NOS inhibition actuates endothelial-mesenchymal transformation

O’Riordan

Mendelev²,

Patschan³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

123

View full text Add to dashboard Cite

Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-beta and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (alpha-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-beta and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.

show abstract

“…UUO was performed on pathogen free male ED-1 mice (8 weeks) by ligation of the left ureter as previously described (12,13). To study the effect of delayed PAI-1 inhibition on TIF, the treatment with PAI-1 decoy peptide mix was initiated on day 3 of UUO by daily iv injection of decoy mixture (1 mg/kg/d).…”

Section: Methodsmentioning

confidence: 99%

“…Parts of kidney were fixed in Carnoy's solution, dehydrated, embedded in paraffin and then sectioned at 3 lm. Then they were subjected to evaluate interstitial fibrosis by immunohistochemical staining collagen III, collagen IV and fibronectin for ECM detection, F4/80 for macrophages detection and a-smooth muscle actin (a-SMA) for myofibroblasts detection, as previously described (12,13). Histomorphometric analyses were performed as previously described (12,13).…”

Section: Methodsmentioning

confidence: 99%

Delayed Treatment with Plasminogen Activator Inhibitor-1 Decoys Reduces Tubulointerstitial Fibrosis

Gonzalez

Klein

Chauhan

et al. 2009

Exp Biol Med (Maywood)

Self Cite

View full text Add to dashboard Cite

We examined the capacity of delayed inhibition of plasminogen activator inhibitor-1 (PAI-1) to reduce tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. Small peptides mimicking parts of urokinase (uPA) and tissular plasminogen activator (tPA) and serving as decoy molecules for PAI-1 were administered daily during the late stages (3 to 8 days) of UUO. Treatment with PAI-1 decoys reduced interstitial deposition of fibronectin, collagen III and collagen IV without changes in macrophage and myofibroblast infiltration. Interestingly, while PAI-1 activity was reduced and the combined uPA and tPA activity was increased, the antifibrotic effect was obtained without modification of plasmin activity but with increased of hepatocyte growth factor (HGF) expression. We show for the first time that treatment with small PAI-1 decoy peptides reduces established tubulointerstitial fibrosis. This protective effect probably resulted from increased degradation of the extracellular matrix by an HGF dependent mechanism.

show abstract

In vivo bradykinin B2 receptor activation reduces renal fibrosis

Cited by 36 publications

References 34 publications

The therapeutic potential of bradykinin B2 receptor agonists in the treatment of cardiovascular disease

The therapeutic potential of bradykinin B2 receptor agonists in the treatment of cardiovascular disease

Chronic NOS inhibition actuates endothelial-mesenchymal transformation

Delayed Treatment with Plasminogen Activator Inhibitor-1 Decoys Reduces Tubulointerstitial Fibrosis

Contact Info

Product

Resources

About