Novel molecular targets and therapeutic strategies for monitoring and preventing necroinflammation in acute kidney injury

• Autores: Juan Guerrero Mauvecin
• Directores de la Tesis: Ana Belén Sanz Bartolomé (dir. tes.), Alberto Ortiz Arduan (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2025
• Idioma: inglés
• Títulos paralelos:
  • Nuevas dianas moleculares y estrategias terapéuticas para la monitorización y prevención de la necroinflamación en la lesión renal aguda
• Tribunal Calificador de la Tesis: Beatriz Suárez Álvarez (presid.), Ana Belén García Redondo (secret.), Lucie Hénaut (voc.), Juan Antonio Moreno Gutiérrez (voc.), Gema Ruiz Hurtado (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Química
    • Bioquímica
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Acute Kidney Injury (AKI) represents a clinical challenge due to its heterogeneous aetiology, limited diagnostic tools, and lack of effective therapeutic options. This thesis explores novel molecular targets and therapeutic strategies, focusing on two key characteristics of AKI: tubular cell death and inflammation. Ferroptosis, a lipid peroxidation-driven form of programmed cell death, is known to cause tubular cell death in different models of AKI. We have characterized the dynamics of this pathway in the tubular cell. A high content on polyunsaturated fatty acids (PUFA) sensitizes tubular cells to ferroptosis, and ACSL4 and ALOX15 have been identified as critical mediators. We found that these enzymes regulate the accumulation of lipid hydroperoxides in tubular cells in presence of ferroptotic stimuli and are upregulated in kidneys of mice with Folic acid-induced AKI (FA-AKI). Targeting of these proteins prevented tubular ferroptosis and reduced kidney injury during AKI, holding significant promise to develop both novel diagnosis and therapeutic strategies. Receptor-Interacting Protein Kinase 3 (RIPK3), a key regulator of necroptosis, a form of regulated necrosis, can also mediate an inflammatory response independent of necroptosis. We examined the inflammatory response during cytokine storm-induced AKI (CS-AKI) following administration of bacterial lipopolysaccharide (LPS). RIPK3 emerged as a significant player in driving inflammation and kidney dysfunction in CS-AKI, extending beyond its well-established role in cell death pathways. Importantly, the expression of IL-6 was found to be significantly modulated by RIPK3 during CS-AKI, specifically within bone marrow cells. In brief, our findings established a novel RIPK3-IL6 axis in which RIPK3 activity within bone marrow cells increases systemic IL-6, which subsequently exerts deleterious effects on the kidney, culminating in local inflammation and exacerbation of kidney dysfunction. Furthermore, the therapeutic potential of targeting the RIPK3-IL6 axis was explored. Treatment with tocilizumab, an anti-IL-6 receptor antibody, effectively attenuated kidney inflammation and injury in preclinical models of CS-AKI, providing evidence for the therapeutic potential of targeting this inflammatory axis. Lastly, therapeutic evaluation of novel GSK inhibitors targeting RIPK1 and RIPK3 demonstrated efficacy in modulating both necroptosis and inflammation. The dual RIPK1/RIPK3 inhibitor GSK’074 and the RIPK1-specific GSK’772 inhibitor exhibited protective effects in cellular models of necroptosis and apoptosis and in animal models of CS-AKI, holding potential against two key mechanisms of AKI. In conclusion, this thesis highlights the significance of ferroptosis and inflammation in two different aetiologies of AKI and identifies key mediators of these mechanisms: the ferroptotic enzymes ACSL4 and ALOX15, as well as the inflammatory axis RIPK3-IL6. Additionally, this research underscores the therapeutic potential of previously unexplored GSK inhibitors in targeting RIPK1/RIPK3-mediated mechanisms in the renal context, thus supporting their potential as novel and effective therapeutic strategies for the management of AKI