Browsing by Author "Espinoza, Sofía"

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    Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury
    (Springer Nature, 2025) Perez-Moreno, Elisa; Peña, Adely de la; 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 González, Teo; González, Alfonso; Soza, Andrea
    Background 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‑galactosidebinding 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. Methods To investigate the endogenous role of Gal‑8 in AKI, we compared the responses of Gal‑8 knockout (Gal8‑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. Results 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. Conclusions 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.
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    Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG
    (2020) Espinoza, Sofía; Barake Sabbagh, M. Francisca; Carvajal Cachaña, Francisco Javier; Segovia Miranda, Fabián Josué; Cerpa Nebott, Waldo Francisco; González de la Rosa, Alfonso; Arredondo, Sebastián B.; Guerrero, Fernanda G.; Valenzuela, David M.; Wyneken, Ursula
    Abstract Background Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Results Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. Conclusions NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.