Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Nephron. 2024;148(10):712-723. doi: 10.1159/000538241. Epub 2024 Mar 8.
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
补体系统是先天免疫防御的基石，通常可提供针对病原体的保护。然而，在各种临床情况下，补体的防御作用可能会损害宿主细胞，从而加剧免疫和炎症反应。在补体激活过程中，中心成分 C3 和 C5 经历蛋白水解切割，产生小的活性片段 C3a 和 C5a 过敏毒素。传统上，这些片段通过特定的受体 C3a 受体 (R)、C5aR1 和 C5aR2 与炎症相关。然而，最近的研究结果强调了过量的 C3a/C3aR 和 C5a/C5aR1 信号作为多种炎症和自身免疫病因疾病的罪魁祸首。这在几种肾脏疾病中尤其如此，其受体在肾脏中的表达增强以及血浆和尿液中 C3a 和 C5a 的高浓度支持了过敏毒素在肾脏损伤中的潜在作用。此外，肾脏细胞合成 C3 和 C5，从而导致补体蛋白在肾脏中的产生，这对局部组织损伤有重要贡献。在本综述中，我们讨论了 C3a/C3aR 和 C5a/C5aR 信号在急性和慢性肾脏疾病中的不同方面，并探讨了新兴靶向药物的治疗潜力，以期未来的临床应用。
