Renal β2-adrenoceptor Modulates the Lipopolysaccharide Transport System in Sepsis-induced Acute Renal Failure

Abstract

The aim of this study was to define the contribution of renal beta(2)-adrenoceptor (beta(2)-AR) system to regulation of the lipopolysaccharide (LPS) transport system in the kidney of endotoxin-induced septic rats. Seven-week-old Wistar rats (n = 6/groups) pre-treated with the beta(2)-AR antagonist (ICI118,551: 3.14 microg/kg) or saline were injected with LPS (10 mg/kg i.p.) or saline, and then 24 hours later, renal function, beta(2)-AR signaling proteins, innate immune proteins, and cytokines were assayed. The injection of LPS depressed creatinine clearance rate (Ccr) associated with the reduction of renal Gsalpha and cAMP levels by a single dose of ICI118,551. On the other hand, renal CD14, toll-like receptor 4(TLR4), and tumour necrosis factor (TNF)-alpha protein expressions were significantly increased (P < 0.05) by the combination of LPS and ICI118,551. The reduction of Ccr by LPS plus ICI118,551 suggests a possibility that renal specific up-regulation of the CD14-TLR4-TNF-alpha signaling cascade by beta(2)-AR inhibition might be involved in sepsis-induced ARF.

Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia

“…Despite this hypotension, creatinine clearance remained unchanged, indicating that GFR was not affected. Previous studies also showed that creatinine clearance was preserved 24 h after LPS injection in Wistar rats (24). It is important to highlight that the triggering of AKI does not require renal hemodynamic alterations (1).…”

“…Thus, our prolonged treatment might have allowed the cytokine levels return back to normal. Besides, the unchanged cytokine levels could also be related to the maintenance of GFR after LPS injection, since they contribute to systemic hypotension and renal injury (24). Plasma NO greatly reduced in endotoxemic group, indicating that NO-independent mechanisms maintained the hypotension, like prostacyclin pathway.…”

“…The host's immune system recognizes endotoxins from Gram-negative bacteria, which are chemically classified as lipopolysaccharides (LPS). In the cell membrane, LPS binds to the acceptor CD14 and the Toll-like receptor 4 (TLR-4) triggers an intracellular signaling that leads to proinflammatory cytokines release, like interleukin-1␤ (IL-1␤), 6 (IL-6), and tumor necrosis factor-␣ (TNF-␣) (17,24,26,31). Systemic releasing of endotoxins and increased expression of TLR-4 in nonimmune cells may initiate secondary responses that contribute to septic shock by increasing nitric oxide (NO) production and vascular permeability, leading to systemic hypotension.…”

Toll-Like Receptors and their Role in Renal Pathologies

“…Human proximal tubular epithelial cell death due to sepsis/inflammation showed characteristics of both necrosis and apoptosis, where necrosis was primarily attributable to LPS stimulation, while CD14 was required for induction of renal cell apoptosis [62]. Injection of LPS in pretreated rats with an antagonist of renal beta2adrenoreceptor (modulator of LPS transport in the kidney), decreased creatinine clearance combined with a significant increase in expression of TLR4, CD14 and TNF- [64]. Injection of LPS in pretreated rats with an antagonist of renal beta2adrenoreceptor (modulator of LPS transport in the kidney), decreased creatinine clearance combined with a significant increase in expression of TLR4, CD14 and TNF- [64].…”

Acute kidney injury: what part do toll-like receptors play?

“…46 LPS injection in pretreated rats with an antagonist of renal beta2-adrenoreceptor (modulator of LPS transport in the kidney), decreased creatinine clearance combined with a significant increase in the expression of TLR4, CD14, and tumor necrosis factor alpha. 59 Concurrently, soluble MD2 was found to be increased in the serum and urine of septic patients, and this molecule has been shown to increase TLR4 activation of the receptor in human embryonic kidney epithelial cells in response to LPS. 60 Septic AKI is an important clinical syndrome characterized by an abnormal hydroelectrolytic and acid base balance, and it is defined by the simultaneous presence of acute renal failure and sepsis.…”