Perez-Moreno Elisa, de la Peña Adely, Toledo Tomás, Saez Javiera, Pérez-Molina Francisca, Espinoza Sofía, Metz Claudia, Díaz-Valdivia Nicole, Azócar Lorena, Prado Carolina, Pacheco Rodrigo, Segovia-Miranda Fabian, Godoy Alejandro S, Amador Cristian A, Feuerhake Teo, González Alfonso, Soza Andrea
Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
Mol Med. 2025 May 16;31(1):192. doi: 10.1186/s10020-025-01245-y.
Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin-8 (Gal-8), a tandem-repeat β-galactoside-binding lectin, plays a role in epithelial cell proliferation, epithelial-mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal-8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear.
To investigate the endogenous role of Gal-8 in AKI, we compared the responses of Gal-8 knockout (Gal-8-KO; Lgals8 bearing a β-gal cassette under the Lgals8 gene promoter) and wild-type (Lgals8) mice in a nephrotoxic folic acid (FA)-induced AKI model. Renal Gal-8 expression was assessed by β-galactosidase staining, lectin-marker colocalization, and RT-qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro-inflammatory T cells.
Galectin-8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8 and Lgals8 mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8 mice showed slightly worse damage. By the fibrotic phase, Lgals8 mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8 mice.
Endogenous Gal-8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating extracellular matrix homeostasis and mitigating fibrosis. Additionally, Gal-8 contributes to inflammation resolution by limiting persistent immune cell infiltration, particularly IL-17-secreting cells.
急性肾损伤（AKI）是一种严重的临床病症，其特征为肾功能迅速下降，常进展为慢性肾脏病（CKD）和纤维化。影响肾损伤恢复或适应性不良修复的内源性机制仍知之甚少。半乳糖凝集素-8（Gal-8）是一种串联重复的β-半乳糖苷结合凝集素，在上皮细胞增殖、上皮-间质转化和免疫调节中发挥作用，所有这些在急性肾损伤的转归中都至关重要。虽然外源性给予Gal-8已显示出肾脏保护作用，但其在肾损伤进展和恢复中的内源性作用仍不清楚。
为了研究Gal-8在急性肾损伤中的内源性作用，我们在肾毒性叶酸（FA）诱导的急性肾损伤模型中比较了Gal-8基因敲除（Gal-8-KO；在Lgals8基因启动子下携带β-半乳糖苷酶盒的Lgals8）小鼠和野生型（Lgals8）小鼠的反应。通过β-半乳糖苷酶染色、凝集素标记共定位和逆转录定量聚合酶链反应（RT-qPCR）评估肾脏Gal-8表达。在损伤的急性期（第2天）和纤维化期（第14天）评估肾功能、结构和免疫反应。测量血浆肌酐水平以评估肾功能，同时组织学分析评估肾小管损伤、肾脏炎症和细胞外基质沉积。进行流式细胞术以表征免疫反应，重点关注促炎性T细胞。
半乳糖凝集素-8主要在肾皮质表达，定位于肾小管、肾小球和血管，急性肾损伤后其水平下降一半。在急性期，Lgals8和Lgals8小鼠均表现出相似的肾功能和结构损害，尽管Lgals8小鼠的损伤稍严重。到纤维化期，Lgals8小鼠表现出更明显的皮质损伤和纤维化，其特征为I型和III型胶原沉积增加以及Th17细胞浸润增强，而成肌纤维细胞活化与Lgals8小鼠相当。
内源性Gal-8在急性期对肾脏没有显著保护作用，对于急性肾损伤后的细胞增殖和死亡并非必需。然而，它在通过调节细胞外基质稳态和减轻纤维化来防止适应性不良修复方面至关重要。此外，Gal-8通过限制持续的免疫细胞浸润，特别是分泌白细胞介素-17的细胞，有助于炎症消退。
