Thromboxane Receptor Mediates Renal Vasoconstriction and Contributes to Acute Renal Failure in Endotoxemic Mice

Abstract

Abstract. Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA 2 ) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPSinduced sepsis. This study tested whether TxA 2 receptor blockade, with the use of TxA 2 receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P Ͻ 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA 2 on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P Ͻ 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P Ͻ 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P Ͻ 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P Ͻ 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P Ͻ 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.

Maintenance of Renal Vascular Reactivity Contributes to Acute Renal Failure during Endotoxemic Shock

“…The constriction involves the preglomerular vasculature (20,21). Furthermore, we have demonstrated using both thromboxane (TxA 2 ) receptor knockout mice and a TxA 2 receptor antagonist that TxA 2 receptors mediate the increased RVR and contribute to the reduced GFR during endotoxemic shock (19). Other studies highlight the role of endothelin and the cytokine TNF-␣ in sepsis-induced ARF (22,23).…”

“…Although endotoxin injection and cecal ligation and puncture, an alternative sepsis model, vary by different cytokine kinetics, both models seem to induce ARF with common signaling pathways and similar sensitivity to therapeutic targets (32). We slightly adapted the initial experimental conditions by increasing the LPS dose to 8.5 mg/kg to mimic more closely septic shock in humans as described previously (19). For this reason, we focused on a relatively late phase of sepsis to simulate a short time-window of undiagnosed clinical sepsis during which one would determine whether drugs that are used routinely, such as NE, or more recently tested (NOS inhibition, AVP) in human septic shock would ameliorate LPSinduced reductions in GFR.…”

“…A marked decrease in renal blood flow (RBF) results from an increase in renal vascular resistance (RVR) in the face of hypotension after LPS injection. This early renal vasoconstriction is accompanied by a low mean arterial pressure (MAP) that persists from 1 to 14 h of observation after LPS administration (19). The constriction involves the preglomerular vasculature (20,21).…”

Distinct Roles for Basal and Induced COX-2 in Podocyte Injury

“…Although selective COX-2 inhibitors have been shown to decrease proteinuria and retard progressive glomerular injury in experimental models of kidney disease, 22 the associated cardiovascular risks preclude the therapeutic use of COX-2 inhibitors in progressive renal injury. Thromboxane A 2 and thromboxane receptor activation mediate renal vasoconstriction and contribute to the pathogenesis of angiotensin-IIdependent hypertension, 23 progression of diabetic nephropathy, 24 -27 and renal failure in endotoxemic mice 28 or rats with 5/6 nephrectomy. 29 Older studies suggested that thromboxane synthase inhibitors or receptor antagonists were efficacious in streptozotocin-induced renal damage, 30 lupus nephritis, [31][32][33] cyclosporine nephrotoxicity, 34 -36 remnant kidney, 37 and renal allograft rejection.…”

Short-term ANG II produces renal vasoconstriction independent of TP receptor activation and TxA2/isoprostane production

“…Also, basal levels of TxA 2 contribute little to tubuloglomerular feedback-induced renal vasoconstriction in normotensive rats (7). Furthermore, basal RBF and RVR are in the normal range in TP receptor null mice (5).…”