Kaminska Marta, Kałucka Urszula, Babickova Janka, Benedyk-Machaczka Małgorzata, Skandalou Eleni, Grant Melissa M, Marti Hans-Peter, Mydel Piotr
Department of Microbiology, Jagiellonian University, Krakow, 30-387, Poland.
Broegelmann Research Laboratory, Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, N-5021, Norway.
BMC Biol. 2025 Mar 12;23(1):76. doi: 10.1186/s12915-025-02187-x.
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.
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 B 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.
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.
尿毒症对伤口愈合的损害是一个已被充分证实的现象，然而这种情况的病因仍然是一个医学谜团。氨甲酰化是一种在尿毒症环境中高频发生的翻译后修饰（PTM），已知其会影响蛋白质和肽的结构及功能特性。在此我们表明，在伤口愈合过程中起关键作用的激肽 - 激肽释放酶系统成员的氨甲酰化，会导致其功能异常，并阻碍尿毒症患者组织再生的复杂过程。
通过酶促测定，我们证明激肽原的氨甲酰化会导致异常的缓激肽生成。我们证实缓激肽在尿毒症条件下以及被活化的中性粒细胞作用下会有效地发生氨甲酰化。此外，这种修饰会影响该肽的蛋白水解切割，可能导致氨甲酰化形式的积累。修饰后的肽对其受体的亲和力较低。氨甲酰化降低了缓激肽刺激伤口愈合过程中必需的B受体和细胞因子表达的能力。与天然形式相比，氨甲酰化缓激肽在促进血管生成和角质形成细胞迁移方面的效力显著降低。在伤口愈合的体内小鼠模型中，我们观察到在存在氨甲酰化形式的情况下，胶原纤维生成受损且上皮再形成延迟。
氨甲酰化驱动的伤口愈合受损是尿毒症中伤口持续存在的一个机制性联系。重要的是，在局部炎症环境中产生氨甲酰化缓激肽可能是糖尿病或银屑病中伤口愈合延迟和慢性伤口形成的一个重要因素。
