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논문분류	춘계학술대회 초록집
제목	Binding ability of recombinant uromodulin fragments to complement factor H and its regulation mechanism on complement alternative pathway
저자	Qiuyu Xie
출판정보	2024; 2024(1):
키워드
초록	Objectives: Uromodulin is the most abundant protein in the urine. It contains three epidermal growth factor-like domains, one D8C domain, one zona pellucida domain, and GPI anchoring region. Complement factor H (cFH) can accelerate the degradation of C3 invertase as a cofactor of complement factor I, which can be enhanced by uromodulin. Autosomal dominant tubulointerstitial kidney disease associated with uromodulin (ADTKD-UMOD) is a hereditary kidney disease, characterized by tubule atrophy and interstitial fibrosis. We explore the binding sites of uromodulin and cFH and their effect on the function of cFH and understand the role of the binding of uromodulin and cFH in kidney diseases. Methods: The uromodulin fragment (UMOD-FLR1) were constructed and expressed. It were then site-directed mutated according to the ADTKD-UMOD patients. The binding affinity of wild type uromodulin fragment with cFH were detected and then compared with the mutant ones by microscale thermophoresis. Further, the effects of wild and mutant fragments on the function of cFH were tested and compared by C3b cleavage and erythrolysis. Patient’s kidney frozen sections were immunostained for complement factor B (indicating activation of complement alternative pathway). Results: The recombinant wild type fragment (UMOD-FLR1) can bind cFH, and the binding affinity was 1.7942x10-6M. UMOD-FLR1 fragment promoted the cleavage of C3b (p＜0.001). The function of mutant fragments with UMOD-FLR1 as the template to promote C3b cracking reduced. Different from UMOD-FLR1 (p=0.026), mutant fragments had no significant inhibition on hemolysis. Complement factor B was positive in the kidney of an ADTKD-UMOD patient. Conclusions: The decrease of binding ability and interaction between recombinant mutant uromodulin according to ADTKD and cFH will lead to insufficient inhibition of complement system, promoting the development of interstitial fibrosis. Supplementing wild type UMOD-FLR1 may be a treatment option.
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