Expression, distribution and function of kinin B<sub>1</sub> receptor in the rat diabetic retina

Hachana, Soumaya; Bhat, Menakshi; Sénécal, Jacques; Huppé-Gourgues, Frédéric; Couture, Réjean; Vaucher, Elvire

doi:10.1111/bph.14138

Cited by 12 publications

(38 citation statements)

References 63 publications

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“…The same dosage of scrambled siRNA (Invitrogen Life Technologies)—same nucleotides as siRNA but in a random sequence—was injected IVT as control. This treatment with IVT B 1 receptor siRNA (10 nmol) resulted in the absence of B 1 receptor protein, by immunohistochemistry, in the streptozotocin (STZ)‐diabetic rat retina and confirmed the specificity of the polyclonal rabbit antiserum for rat B 1 receptors (Hachana et al, ). The latter study also showed the efficacy of the B 1 receptor siRNA in reducing the mRNA levels of kinin receptors (B 1 receptors and B 1 receptors), VEGF‐A, and VEGFR‐2 in the retinas of STZ‐diabetic rats by quantitative RT‐PCR.…”

Section: Methodssupporting

confidence: 56%

“…The same dosage of a normal goat IgG (AB‐108C, R&D systems) was injected as control. Induction and up‐regulation of B 1 receptors was blocked with 10 nmol of an IVT injection of B 1 receptor siRNA (Ambion Invitrogen Life Technologies, Canada; Hachana et al, ). The same dosage of scrambled siRNA (Invitrogen Life Technologies)—same nucleotides as siRNA but in a random sequence—was injected IVT as control.…”

Section: Methodsmentioning

confidence: 99%

“…It was topically administered (≈100 μg/10 μl −1 ) twice a day to the surface of the eye in non‐anaesthetized rats for 10 days, starting immediately after the CNV. Using radiolabelled [ 3 H]‐R‐954, R‐954 was found to diffuse to the retina within 1 hr and to remain in the tissue for up to 12 hr after its administration to the ocular surface (Hachana et al, ). As R‐954 is not metabolized in rat tissue homogenates at room temperature (Gobeil et al, ), only its intact form can be found in retina.…”

Section: Methodsmentioning

confidence: 99%

“…Dissected retina including the RPE was visually inspected to exclude cross‐contamination with the vitreous and choroid and was immediately submerged in RNA later stabilization reagent (QIAGEN, Valencia, CA, USA). SYBR green‐based real‐time quantitative PCR using the Mx3000p device for signal detection was performed as described previously (Hachana et al, ; Pouliot et al, ). Duplicates were used to ensure the reliability of single values.…”

Section: Methodsmentioning

confidence: 99%

“…A role for the KKS was previously described in diabetic retinopathy (Feener, ; Pouliot et al, ). For example, activation of B 1 receptors enhances vascular permeability, leukocyte adhesion, and the expression of pro‐inflammatory molecules such as VEGF‐A, VEGF‐R2, ICAM‐1, VCAM‐1, COX‐2, and IL‐1β in the diabetic retina (Hachana et al, ; Pouliot et al, ). In addition to its effects on inflammation, BK promotes angiogenesis by up‐regulating basic FGF (bFGF) via B 1 receptors and by stimulating VEGF formation via B 2 receptors in a non‐ocular model of neovascularization (Colman, ).…”

Section: Introductionmentioning

confidence: 99%

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The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Hachana

Fontaine

Sapieha

et al. 2020

British J Pharmacology

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Background and Purpose: Age-related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti-VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro-inflammatory kallikreinkinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti-VEGF and anti-B 1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV). Experimental Approach: Immediately after laser-induced CNV, Long-Evans rats were treated by eye-drop application of a B 1 receptor antagonist (R-954) or by intravitreal injection of B 1 receptor siRNA or anti-VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood-retinal barrier was measured 10 days later in the retina. B 1 receptor and VEGF-R2 cellular localization was assessed. Key Results: The three treatments significantly inhibited the CNV-induced retinal changes. Anti-VEGF and R-954 decreased CNV-induced up-regulation of B 1 and B 2 receptors, TNF-α, and ICAM-1. Anti-VEGF additionally reversed up-regulation of VEGF-A, VEGF-R2, HIF-1α, CCL2 and VCAM-1, whereas R-954 inhibited gene expression of IL-1β and COX-2. Enhanced retinal vascular permeability was abolished by anti-VEGF and reduced by R-954 and B 1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti-VEGF and B 1 receptor inhibition. B 1 receptors were found on astrocytes and endothelial cells.Conclusion and Implications: B 1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser-induced CNV. The non-invasive, selfadministration of B 1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.

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Section: Methodssupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Hachana

Fontaine

Sapieha

et al. 2020

British J Pharmacology

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Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Dubuc

Savard

Bovenzi

et al. 2018

Journal Cellular Physiology

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High nuclear expression of G protein-coupled receptors, including kinin B1 receptors (B1R), has been observed in several human cancers, but the clinical significance of this is unknown. We put forward the hypothesis that these "nuclearized" kinin B1R contribute to tumorigenicity and can be a new target in anticancer strategies. Our initial immunostaining and ultrastructural electron microscopy analyses demonstrated high B1R expression predominantly located at internal/nuclear compartments in the MDA-MB-231 triple-negative breast cancer (TNBC) cell line as well as in clinical samples of patients with TNBC. On the basis of these findings, in the present study, we evaluated the anticancer therapeutic potential of newly identified, cell-permeable B1R antagonists in MDA-MB-231 cells (ligand-receptor binding/activity assays and LC-MS/MS analyses). We found that these compounds (SSR240612, NG67, and N2000) were more toxic to MDA-MB-231 cells in comparison with low- or non-B1R expressing MCF-10A normal human mammary epithelial cells and COS-1 cells, respectively (clonogenic, MTT proliferative/cytocidal assays, and fluorescence-activated cell-sorting (FACS)-based apoptosis analyses). By comparison, the peptide B1R antagonist R954 unable to cross cell membrane failed to produce anticancer effects. Furthermore, the putative mechanisms underlying the anticancer activities of cell-penetrant B1R antagonists were assessed by analyzing cell cycle regulation and signaling molecules related to cell survival and apoptosis (FACS and western blot). Finally, drug combination experiments showed that cell-penetrant B1R antagonists can cooperate with suboptimal doses of chemotherapeutic agents (doxorubicin and paclitaxel) to promote TNBC death. This study provides evidence on the potential value of internally acting kinin B1R antagonists in averting growth of breast cancer.

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Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors

et al. 2023

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Objective and design After traumatic skeletal muscle injury, muscle healing is often incomplete and produces extensive fibrosis. Bradykinin (BK) reduces fibrosis in renal and cardiac damage models through the B2 receptor. The B1 receptor expression is induced by damage, and blocking of the kallikrein-kinin system seems to affect the progression of muscular dystrophy. We hypothesized that both kinin B1 and B2 receptors could play a differential role after traumatic muscle injury, and the lack of the B1 receptor could produce more cellular and molecular substrates for myogenesis and fewer substrates for fibrosis, leading to better muscle healing. Material and methods To test this hypothesis, tibialis anterior muscles of kinin receptor knockout animals were subjected to traumatic injury. Myogenesis, angiogenesis, fibrosis, and muscle functioning were evaluated. Results Injured B1KO mice showed a faster healing progression of the injured area with a larger amount of central nucleated fiber post-injury when compared to control mice. In addition, they exhibited higher neovasculogenic capacity, maintaining optimal tissue perfusion for the post-injury phase; had higher amounts of myogenic markers with less inflammatory infiltrate and tissue destruction. This was followed by higher amounts of SMAD7 and lower amounts of p-SMAD2/3, which resulted in less fibrosis. In contrast, B2KO and B1B2KO mice showed more severe tissue destruction and excessive fibrosis. B1KO animals had better results in post-injury functional tests compared to control animals. Conclusions We demonstrate that injured skeletal muscle tissues have a better repair capacity with less fibrosis in the presence of B2 receptor and absence of B1 receptor, including better performances in functional tests.

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Expression, distribution and function of kinin B₁ receptor in the rat diabetic retina

Abstract: Our results support the detrimental role of B receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.

Cited by 12 publications

References 63 publications

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors

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Expression, distribution and function of kinin B1 receptor in the rat diabetic retina

Abstract: Our results support the detrimental role of B receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.

Cited by 12 publications

References 63 publications

The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Antitumor activity of cell‐penetrant kinin B1 receptor antagonists in human triple‐negative breast cancer cells

Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors

Contact Info

Product

Resources

About

Expression, distribution and function of kinin B₁ receptor in the rat diabetic retina

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization