Title:Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: a New Target for Sepsis
Volume: 19
Issue: 8
Author(s): Sebastian Gatica, Felipe Eltit, Juan F. Santibanez, Diego Varela, Claudio Cabello-Verrugio and Felipe Simon*
Affiliation:
- Departamento de Ciencias Biologicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, 8370146, Santiago,Chile
Keywords:
Endotoxemia, TRPM7, cytokine, sepsis, organ dysfunction, MODS.
Abstract:
Background: Main pathological features detected during sepsis and
endotoxemia include over-secretion of pro-inflammatory cytokines and multiorgan
dysfunction syndrome (MODS). Unfortunately, current clinical efforts to treat sepsis are
unsatisfactory, and mortality remains high. Interestingly, transient receptor potential
(TRP) melastatin 7 (TRPM7) ion channel controlling Ca2+ and Mg2+ permeability is
involved in cytokine production and inflammatory response. Furthermore, TRPM7
downregulation has been shown to alleviate local symptoms in some models of sepsis,
but its effects at a systemic level remain to be explored.
Objective: To test whether TRPM7 mediates cytokine production and MODS during
endotoxemia.
Methods: Endotoxemic and sham-endotoxemic rats were subjected to pharmacological
inhibition of TRPM7 using carvacrol, or to expression suppression by adenovirus
delivery of shRNA (AdVshTRPM7). Then, cytokine and MODS levels in the blood were
measured.
Results: Inhibition of TRPM7 with carvacrol and suppression with AdVshTRPM7 were both
efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-α, IL-1β, IL-6,
and IL-12, in endotoxemic rats, without inducing downregulation in blood levels of antiinflammatory
cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdVshTRPM7
significantly prevented liver and pancreas dysfunction, altered metabolic function, and
hypoglycemia, induced by endotoxemia. Furthermore, muscle mass wasting and cardiac
muscle damage were also significantly reduced by the use of carvacrol and AdVshTRPM7
in endotoxemic rats.
Conclusion: Our results indicate TRPM7 ion channel as a key protein regulating
inflammatory responses and MODS during sepsis. Moreover, TRPM7 appears as a
novel molecular target for the management of sepsis.
