Prevention of sepsis-induced renal proximal tubular cell injury: prostaglandin uptake transporter PGT as a therapeutic target
The increase during sepsis in the plasma levels of inflammatory cytokines may result in renal proximal tubular cell (PTC) injury, thereby contributing to acute renal injury and mortality. Our preliminary results suggest that an increase in intracellular prostaglandin E2, triggered by cytokines such as TNF-α, IFN-γ, IL-2 e IL-1β (which are frequently increased in plasmas from septic patients) plays a relevant role in cytokine-induced PTC injury. Therefore, inhibitors of prostaglandin reuptake transporter PGT such as bromosulfophthalein would protect PTC against the noxious effects of inflammatory cytokines during sepsis.
The present project is aimed to confirm that i) plasmas from septic patients induce PTC injury and that both inflammatory cytokines and intracellular prostaglandin E2 play a relevant role in PTC injury and ii) that bromosulfophthalein prevents PTC injury sepsis-induced PTC injury in vivo (bacterial lipopolysaccharide murine model of sepsis) as well as in vitro (PTC injury by inflammatory cytokynes).
The expected results will help to understand how are directly injured PTC by inflammatory cytokines during sepsis, to assess the efficacy of bromosulfophthalein in the prevention of inflammatory cytokine-induced PTC injury and to stablish the scientific basis of and the therapeutic utility of the pharmacological inhibition of the PGT transporter.