Protective effect of renal denervation on normotensive endotoxemia-induced acute renal failure in mice

Abstract

Protective effect of renal denervation on normotensive endotoxemia-induced acute renal failure in mice. Am J Physiol Renal Physiol 283: F583-F587, 2002. First published March 12, 2002 10.1152/ajprenal.00270.2001.-Acute renal failure (ARF) contributes substantially to the high morbidity and mortality observed during endotoxemia. We hypothesized that selective blockade of the renal nerves would be protective against ARF during the early (16 h) stage of endotoxemia [5 mg lipopolysaccharide (LPS)/kg ip in mice]. At 16 h after LPS, there was no change in mean arterial pressure, but plasma epinephrine (4,604 Ϯ 719 vs. 490 Ϯ 152 pg/ml, P Ͻ 0.001), norepinephrine (2,176 Ϯ 306 vs. 1,224 Ϯ 218 pg/ml, P Ͻ 0.05), and plasma renin activity (40 Ϯ 5 vs. 27 Ϯ 2 ng⅐ ml Ϫ1 ⅐ h Ϫ1 , P Ͻ 0.05) were higher in the LPStreated vs. control mice. The high plasma renin activity level decreased to the control level with renal denervation in endotoxemic mice. After intravenous injection of phentolamine (200 g/kg), the decrement in mean arterial pressure was significantly greater in LPS-treated vs. control mice (19.4 Ϯ 3.5 vs. 8.1 Ϯ 1.5 mmHg, P Ͻ 0.01). Sixteen hours after LPS administration, there were significant decreases in glomerular filtration rate (52 Ϯ 18 vs. 212 Ϯ 23 l/min, P Ͻ 0.01) and renal blood flow (0.58 Ϯ 0.08 vs. 0.85 Ϯ 0.06 ml/min, P Ͻ 0.01) in sham-operated mice. The decrement in glomerular filtration rate during endotoxemia was significantly attenuated in mice with denervated kidneys (32 vs. 79%). Moreover, there was no change in renal blood flow during endotoxemia in mice with renal denervation. The present results therefore demonstrate a protective role of renal denervation during normotensive endotoxemia-related ARF in mice, an effect that may be, at least in part, due to a diminished activation of the renin-angiotensin system. glomerular filtration rate; renal blood flow; epinephrine; norepinephrine; sepsis SEPSIS IS THE MOST FREQUENT CAUSE of acute renal failure (ARF) in intensive care units (1, 2, 9). When sepsis is associated with ARF, the mortality may be as high as 80%. The pathogenetic factors responsible for sepsisrelated ARF, however, are incompletely defined. Although ARF may occur with septic shock, it is also clear that sepsis-related ARF can occur in the absence of hypotension (1, 11).In recent studies from our laboratory, a mouse model of endotoxemia-related ARF has been studied. A significant decrease in glomerular filtration rate (GFR) and renal blood flow (RBF) occurs in the absence of a fall in blood pressure (7). We hypothesized that endotoxemia may be associated with normal blood pressure because of activation of the sympathetic nervous system and renin-angiotensin system (RAS), which secondarily causes renal vasoconstriction. The roles of renal nerves and the RAS in this early renal vasoconstriction during endotoxemia, however, have not been investigated. The present investigation was therefore undertaken in a normotensive mouse model of endotoxemia-induced ARF to examine the effect of selective r...

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

“…The role of TP receptor on renal hemodynamic changes was studied in a standard experimental model of sepsis (3,9). The relevance of this model was recently highlighted by the discovery of LPS signaling pathways leading to inducible nitric oxide synthase (iNOS) and COX-2 gene stimulation (24,25).…”

“…ARF independent of sepsis increases morbidity and mortality (2). During sepsis, an enhancement of renal vascular resistance (RVR) is common, largely independent of a change in mean arterial pressure (MAP) (3). In this regard, renal vasoconstriction markedly contrasts with sepsisinduced generalized systemic vasodilation that includes decreases in MAP and of systemic, intestinal, hepatic, splenic, and nonsplanchnic vascular resistances (4).…”

“…In this regard, plasma renin activity and plasma concentrations of epinephrine and norepinephrine are increased 16 h after LPS injection. Renal denervation protects against endotoxemia-related ARF (3). In addition to the elevated circulatory levels of catecholamines, other vasoconstrictors such as angiotensin II and vasopressin and locally produced thromboxane A2 (TxA 2 ) may play important roles in septic ARF.…”

Determinantes precoces en el desarrollo de injuria renal aguda durante la sepsis abdominal experimental

“…La vasocontricción microvascular renal ha sido descrita previamente como un mecanismo de IRA en la sepsis 21,22 . Esta vasocontricción ha sido explicada por activación del sistema de renina -angiotensina y por un aumento de la actividad nerviosa simpática renal 23,24 . La respuesta inflamatoria característica de la sepsis, se ha estudiado como un mecanismo de IRA en la sepsis 25,26 .…”

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

“…LPS at this dosage did not significantly reduce either conscious BP during the first 8 hours after injection or BP under anesthesia 6 hours after injection (Supplemental Figure 1), confirming the subpressor dose previously reported. 22 Subcutaneous intermittent fluid resuscitation (50 ml/kg saline) 4 and 18 hours after LPS 23 normalized both 24-hour BUN and 24-hour urine output.…”