Activation of the human keratinocyte B1 bradykinin receptor induces expression and secretion of metalloproteases 2 and 9 by transactivation of epidermal growth factor receptor

Matus, Carola E.; Ehrenfeld, Pamela; Pavicic, Francisca; González, Carlos B.; Concha, Miguel; Bhoola, K. D.; Burgos, Rafael A.; Figueroa, Carlos D.

doi:10.1111/exd.13038

Cited by 16 publications

(7 citation statements)

References 59 publications

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“…Cd209 antigens and resistin-like alpha ( Retnla ), which is also found in inflammatory zone 1 ( Fizz 1 ), are considered M2 macrophage markers [ 54 ]. Tissue kallikreins are key genes that promote re-epithelialization [ 55 – 57 ]. Recently, the use of tissue kallikreins and its receptors as therapeutic targets for chronic nonhealing wounds in diabetes attracted attention [ 56 – 59 ].…”

Section: Discussionmentioning

confidence: 99%

Topical estrogen application promotes cutaneous wound healing in db/db female mice with type 2 diabetes

et al. 2022

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Female sex hormones are beneficial effects for wound healing. However, till date, whether topical estrogen application can promote cutaneous wound healing in diabetes remains unclear. Therefore, the present study aimed to validate the effect of topical estrogen application on cutaneous wound healing in a type 2 diabetes db/db mice model. In total, 22 db/db female mice with type 2 diabetes and eight C57BL/6J female mice were subjected to two full-thickness wound injuries. The mice were divided into the db/db, db/db + estrogen, db/db + vehicle, and wild type (WT) groups. Wound healing was assessed until day 14. The db/db group had a significantly high wound area ratio (wound area/initial wound area) on days 3–14 and a significantly low re-epithelialization ratio on days 7 and 14. Moreover, their angiogenesis ratio was significantly low on day 7 and high on day 14. In contrast, compared with the db/db group, the db/db + estrogen group had a significantly lower wound area ratio on days 1–14 and angiogenesis ratio on day 14, thereby indicating early withdrawal of new blood vessels, as well as a significantly higher re-epithelialization ratio on days 7 and 14 and Ym1+ M2 macrophage/macrophage ratio on day 7. Moreover, microarray analysis showed that the top 10 upregulated or downregulated genes in the db/db group were reversed by estrogen treatment, particularly on day 14, in comparison with the WT group. Thus, topical estrogen application reduced the wound area, promoted re-epithelialization and angiogenesis, and increased the number of M2 macrophages in mice with type 2 diabetes. Furthermore, it improved the differential regulation of genes in db/db mice. Therefore, such treatment can enhance cutaneous wound healing in female mice with type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Topical estrogen application promotes cutaneous wound healing in db/db female mice with type 2 diabetes

et al. 2022

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“…Kinin B1 receptor stimulation triggers synthesis and secretion of matrix metalloproteases (MMPs), and subsequent phosphorylation of ERK1/2 and PI3K/AKT [ 44 ]. The MMPs play a crucial role in tissue remodeling through the regulation of extracellular matrix degradation, cell migration, differentiation, and cell proliferation [ 46 ]. In the present study, kinin B1 receptor blockade with BI113823 significantly reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9 and iNOS, and inhibited the phosphorylation of ERK1/2 and AKT, and compared to measurements in vehicle-treated rats.…”

Section: Discussionmentioning

confidence: 99%

Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade

et al. 2021

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Background This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. Methods Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. Results Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1β, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, βMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. Conclusions We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins.

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“…Considering the established role of bradykinin as a hypotensive peptide, it appears that the plasma KKS serves as a physiologic counterbalance to the hypertensive prothrombotic RAS(61).Noteworthy, reciprocal interactions may occur as well, with BK affecting RAAS. Indeed, BK activates ADAM17 via BKB2R(16) and Des-Arg9-bradykinin activates metalloprotease 2 and 9 via BK1-R(18,44), eventually leading to the shedding of ACE2 from cell membranes. This may accelerate the depletion of ACE2 and Ang1-7, on top of ACE2 internalization and degradation, caused by SARS-CoV infection.…”

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confidence: 99%

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Abassi

Skorecki

Hamo-Giladi

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiologic pathways that participate in SARS CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang) 1-7, in maintaining microcirculatory balance and in the control of activated pro-inflammatory and pro-coagulant pathways, generated in this disease, have been clarified. The kalikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiologic pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiologic changes characteristic to this disorder. Herein we outline the current knowledge regarding the reciprocal interactions of RAAS, BK and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R might be explored as potential novel therapeutic strategies in this devastating disorder.

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Activation of the human keratinocyte B1 bradykinin receptor induces expression and secretion of metalloproteases 2 and 9 by transactivation of epidermal growth factor receptor

Cited by 16 publications

References 59 publications

Topical estrogen application promotes cutaneous wound healing in db/db female mice with type 2 diabetes

Topical estrogen application promotes cutaneous wound healing in db/db female mice with type 2 diabetes

Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

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