Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction
Abstract Background Uremic impairment of wound healing is a well-established phenomenon, however the etiology of this condition continues to be a medical enigma. Carbamylation, posttranslational modification (PTM) occurring with high frequency in uremic milieu, is known to have impact on structural...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s12915-025-02187-x |
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| author | Marta Kaminska Urszula Kałucka Janka Babickova Małgorzata Benedyk-Machaczka Eleni Skandalou Melissa M. Grant Hans-Peter Marti Piotr Mydel |
| author_facet | Marta Kaminska Urszula Kałucka Janka Babickova Małgorzata Benedyk-Machaczka Eleni Skandalou Melissa M. Grant Hans-Peter Marti Piotr Mydel |
| author_sort | Marta Kaminska |
| collection | DOAJ |
| description | Abstract Background Uremic impairment of wound healing is a well-established phenomenon, however the etiology of this condition continues to be a medical enigma. Carbamylation, posttranslational modification (PTM) occurring with high frequency in uremic milieu, is known to have impact on structural and functional properties of proteins and peptides. Herein we show that carbamylation of the members of kinin-kallikrein system, that play an essential role in wound healing process, results in its aberrant functionality and impedes the complex process of tissue regeneration in uremic patients. Results Through enzymatic assays we demonstrate that carbamylation of kininogen results in aberrant bradykinin generation. We confirmed that bradykinin is efficiently carbamylated in uremic conditions and, alternatively, by activated neutrophiles. Moreover, this modification affects proteolytic cleavage of the peptide, potentially leading to the accumulation of the carbamylated form. Modified peptide demonstrated lower affinity toward its receptors. Carbamylation diminished bradykinin’s ability to stimulate expression of the B1 receptor and cytokines essential in wound healing process. Carbamylated bradykinin was significantly less potent in promoting angiogenesis and keratinocyte motility as compared to the native form. In the in vivo murine model of wound healing, we observed impaired collagen fiber production and delayed re-epithelialisation in the presence of carbamylated form. Conclusions Carbamylation-driven impairment of wound healing is a mechanistic link to wound persistence in uremia. Importantly, production of carbamylated bradykinin in localized inflammatory milieus could be a significant contributor to delayed wound healing and formation of chronic wounds in diabetes or psoriasis. |
| format | Article |
| id | doaj-art-38bcc1bd635d4b6d8cc3cadfb36df95c |
| institution | DOAJ |
| issn | 1741-7007 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj-art-38bcc1bd635d4b6d8cc3cadfb36df95c2025-08-20T03:01:41ZengBMCBMC Biology1741-70072025-03-0123111310.1186/s12915-025-02187-xBradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunctionMarta Kaminska0Urszula Kałucka1Janka Babickova2Małgorzata Benedyk-Machaczka3Eleni Skandalou4Melissa M. Grant5Hans-Peter Marti6Piotr Mydel7Department of Microbiology, Jagiellonian UniversityDepartment of Microbiology, Jagiellonian UniversityBroegelmann Research Laboratory, Department of Clinical Science, Faculty of Medicine, University of BergenDepartment of Microbiology, Jagiellonian UniversityDepartment of Clinical Medicine, Faculty of Medicine, University of BergenInstitute of Clinical Sciences, University of BirminghamDepartment of Clinical Medicine, Faculty of Medicine, University of BergenDepartment of Microbiology, Jagiellonian UniversityAbstract Background Uremic impairment of wound healing is a well-established phenomenon, however the etiology of this condition continues to be a medical enigma. Carbamylation, posttranslational modification (PTM) occurring with high frequency in uremic milieu, is known to have impact on structural and functional properties of proteins and peptides. Herein we show that carbamylation of the members of kinin-kallikrein system, that play an essential role in wound healing process, results in its aberrant functionality and impedes the complex process of tissue regeneration in uremic patients. Results Through enzymatic assays we demonstrate that carbamylation of kininogen results in aberrant bradykinin generation. We confirmed that bradykinin is efficiently carbamylated in uremic conditions and, alternatively, by activated neutrophiles. Moreover, this modification affects proteolytic cleavage of the peptide, potentially leading to the accumulation of the carbamylated form. Modified peptide demonstrated lower affinity toward its receptors. Carbamylation diminished bradykinin’s ability to stimulate expression of the B1 receptor and cytokines essential in wound healing process. Carbamylated bradykinin was significantly less potent in promoting angiogenesis and keratinocyte motility as compared to the native form. In the in vivo murine model of wound healing, we observed impaired collagen fiber production and delayed re-epithelialisation in the presence of carbamylated form. Conclusions Carbamylation-driven impairment of wound healing is a mechanistic link to wound persistence in uremia. Importantly, production of carbamylated bradykinin in localized inflammatory milieus could be a significant contributor to delayed wound healing and formation of chronic wounds in diabetes or psoriasis.https://doi.org/10.1186/s12915-025-02187-xBradykininWound healingCarbamylationPosttranslational modification |
| spellingShingle | Marta Kaminska Urszula Kałucka Janka Babickova Małgorzata Benedyk-Machaczka Eleni Skandalou Melissa M. Grant Hans-Peter Marti Piotr Mydel Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction BMC Biology Bradykinin Wound healing Carbamylation Posttranslational modification |
| title | Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| title_full | Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| title_fullStr | Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| title_full_unstemmed | Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| title_short | Bradykinin’s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| title_sort | bradykinin s carbamylation as a mechanistic link to impaired wound healing in patients with kidney dysfunction |
| topic | Bradykinin Wound healing Carbamylation Posttranslational modification |
| url | https://doi.org/10.1186/s12915-025-02187-x |
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