Cytokine-mediated regulation of renal urea transporters during sepsis

Background The pathogenesis of endotoxemic tubular dys-function with failure in urine concentration is poorly understood. Urea plays an important role in the urinary concentrating mechanism and expression of the urea transporters UT-A1, UT-A2, UT-A3, UT-A4 and UT-B is essential for tubular urea reabsorption. The present study attempts to assess the regulation of renal urea transporters during severe inflammation in vivo. Materials and methods By agreement of the animal protection committee C57BL/6J, mice were injected with lipopolysaccharides (LPS, 10 mg/kg) or proinflammatory cytokines. Hemodynamic, renal parameters and the expression of renal urea transporters were investigated. To clarify the role of cytokines and renal ischemia in the regulation of renal urea transporters, experiments were performed with cytokine knockout mice, mice treated with low-dose LPS (1, 5 mg/kg) as a sepsis model without induction of hypotension, glucocorticoid-treated mice, and mice with renal artery clipping serving as a model for renal ischemia. Results and discussion LPS-injected mice (10 mg/kg) presented with reduced glomerular filtration rate, fractional urea excretion and inner medulla osmolality associated with a marked decrease in expression of UT-A1, UT-A2, UT-A3, UT-A4 and UT-B (Figure 1). Similar alterations were observed after application of TNFα, IL-1β, IFNγ or IL-6. LPS-induced downregulation of urea transporters was not affected in knockout mice with deficient TNFα, IL-receptor-1, IFNγ or IL-6. Glucocorticoid treatment inhibited LPS-induced increases of tissue TNFα, IL-1β, IFNγ or IL-6 concentration, diminished LPS-induced renal dysfunction and attenuated the downregulation of renal urea transporters. Injection of low-dose LPS (1, 5 mg/kg) also led to renal dysfunction paralleled by a downregulation of renal urea transporters without alterations in blood pressure. Renal ischemia induced by renal artery clipping did not influence the expression of urea transporters. Conclusion Our findings demonstrate downregulation of renal urea transporters that probably accounts for tubular dysfunction during sepsis. Furthermore, they suggest that downregulation of Figure 1 (abstract P1) Effect of lipopolysaccharide (LPS) (10 mg/kg), dexamethasone (10 mg/kg) and the combination of both on UT-A1, UT-A2, UT-A3, UT-A4 and UT-B mRNA in the kidney 6, 12 and 24 hours after intraperitoneal injection. Values are related to signals obtained for β-actin mRNA and presented as the percentage of vehicle control. Mean ± SEM of six animals per group. *P < 0.05 versus control, # P < 0.05 versus LPS treatment. renal urea transporters during LPS-induced acute renal failure is mediated by proinflammatory cytokines and is independent from renal ischemia due to sepsis-induced hypotension. Background …