Department of Physiology, Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel.
Adv Exp Med Biol. 2020;1221:685-702. doi: 10.1007/978-3-030-34521-1_28.
Recent years have brought about fledgling realization of the role played by heparanase in the pathogenesis of diverse diseases including kidney diseases and, specifically, acute kidney injury. Human heparanase-1 is critically and uniquely engaged in cleavage of heparan sulfate, an integral part of glycocalyx and extracellular matrix where it harbors distinct growth factors, cytokines, and other biologically active molecules. The enzyme is induced and activated in acute kidney injury regardless of its causes, ischemic, nephrotoxic, septic or transplantation-related. This event unleashes a host of sequelae characteristic of the pathogenesis of acute kidney injury, such as induction and reinforcement of innate immune responses, predisposition to thrombosis, activation of monocytes/macrophages and remodeling of the extracellular matrix, thus setting up the stage for future fibrotic complications and development of chronic kidney disease. We briefly discuss the emerging therapeutic strategies of inhibiting heparanase, as well as the diagnostic value of detecting products of heparanase activity for prognostication and treatment.
近年来,人们逐渐认识到肝素酶在包括肾脏疾病在内的多种疾病发病机制中的作用,特别是在急性肾损伤方面。人类肝素酶-1在裂解肝素硫酸酯中起着关键而独特的作用,肝素硫酸酯是糖萼和细胞外基质的重要组成部分,其中含有独特的生长因子、细胞因子和其他生物活性分子。无论其病因是缺血性、肾毒性、脓毒症还是与移植相关,急性肾损伤都会诱导和激活该酶。这一事件引发了一系列急性肾损伤发病机制的特征性后果,如先天免疫反应的诱导和增强、易发生血栓形成、单核细胞/巨噬细胞的激活和细胞外基质的重塑,从而为未来的纤维化并发症和慢性肾脏病的发展奠定了基础。我们简要讨论了抑制肝素酶的新兴治疗策略,以及检测肝素酶活性产物对预后和治疗的诊断价值。