Mechanisms of the Urinary Concentration Defect and Effect of Desmopressin During Endotoxemia in Rats

Abstract

Acute renal failure during human sepsis is often nonoliguric. To study the underlying mechanisms, renal function was assessed in endotoxic and control male Wistar rats during and after saline loading and treatment with the selective V2 receptor agonist desmopressin. Escherichia coli endotoxin (dose, 8 mg/kg) was administered from time (t)=0 to t=60 min; saline loading (rate, 5 mL/100 g per hour) was administered from t=0 to t=120 min. Thereafter, half of each group received desmopressin (dose, 10 microg) for 1 h. The inner medullary (IM) osmolality, hematocrit, plasma, and urinary concentrations of sodium, potassium, urea, and osmolality were measured; then, aquaporin 2 (AQP2) immunohistochemistry was performed. Plasma vasopressin concentrations were measured at t=180 min. Saline loading increased urine volume in all rats. In the endotoxic group, mean arterial pressure decreased when saline loading was stopped. Despite increased hematocrit and vasopressin levels (>16 pg/mL), the endotoxin group had a low IM osmolality (mean +/- SEM, 412+/-0.04 mOsm/kg H2O) in comparison with the control group (mean +/- SEM, 1,094+/-0.17 mOsm/kg H2O) and was not able to either decrease urine volume or raise urine osmolality. Desmopressin treatment in endotoxin-treated rats maintained mean arterial pressure, increased sodium reabsorption, IM osmolality, and urine osmolality, and decreased urine flow. The AQP2 intensity decreased in the endotoxin group, and the apical localization disappeared; both were not affected by desmopressin. Our results indicate that endotoxemia in rats acutely diminishes renal urinary concentration capacity and is associated with a decreased IM osmolality and diminished apical AQP2 localization. These findings may help to explain nonoliguric acute renal failure in human septic shock.

Modulation of aquaporin-2/vasopressin2 receptor kidney expression and tubular injury after endotoxin (lipopolysaccharide) challenge*

“…In this study, an increased UO and water clearance were clearly observed using an intraperitoneal endotoxin challenge despite an AVP osmotic pump infusion, which induced a tenfold higher induced AVP plasma concentration. Importantly, this model demonstrated increased kidney AQP-2 apical membrane expression after LPS challenge, contrary to that observed in three studies (31, 32, 34), especially that of Versteilen et al (34) who localized reduced lumen AQP-2, but in a short-term intravenous and fluid-resuscitated model. In addition, AVP-induced enhanced daily urinary excretion of AQP-2, which represents nearly 4% of total kidney expression at baseline (36), was almost completely abolished by LPS challenge.…”

“…This medulla-to-cortex microvascular redistribution is not necessarily apparent by measuring total RBF, and the associated reactivity to vasoconstrictor agents is either normal or increased (29-31). Several hours after challenge, endotoxemia in rats often causes polyuria (31, 32, 34). Indeed, as much as one third of sepsis-induced ARF are polyuric at bedside (33, 34), and when oliguric, acute tubular necrosis is generally suspected (5, 34).…”

“…Several hours after challenge, endotoxemia in rats often causes polyuria (31, 32, 34). Indeed, as much as one third of sepsis-induced ARF are polyuric at bedside (33, 34), and when oliguric, acute tubular necrosis is generally suspected (5, 34). However, acute tubular necrosis is generally lacking at autopsy (5) and minimal or no histologic alterations have been described in a series of patients deceased from sepsis—including half with ARF—and in septic sheep exhibiting ARF (35).…”

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

“…Studies have documented that endotoxemia induced by lipopolysaccharide led to diuresis, downregulation of AQP2 (37,46), and an impaired V2R/AQP2 network as well (7,16), suggesting that proinflammatory cytokines may be involved in the regulation of AQP2 and urinary concentrating defects seen in endotoxemia. IL-1␤, a key proinflammatory cytokine, is produced by macrophages, monocytes, endothelial cells, tubular epithelial cells, and mesangial cells in the kidney.…”

Vasopressin and Its Immune Effects in Septic Shock

“…Indeed, in a rat endotoxin model the V2 agonist desmopressin restored endotoxininduced decreases in sodium reabsorption, inner medulary osmolality and urine osmolality, while decreasing urine flow [52] , suggesting that V2 receptor stimulation plays a beneficial role. In contrast, in an animal model of sepsis which resulted in impaired renal function in the presence of vasopressin, V2 receptors appeared to mediate impaired creatinine clearance [53] .…”