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

Abstract

Objective-Sepsis-induced organ dysfunctions remain prevalent and account for >50% of intensive care unit admissions for acute renal failure with a mortality rate nearing 75%. In addition to the fact that the mechanisms underlying the pathophysiology of sepsis-related acute renal failure are unclear, the impact on septic-induced acute renal failure of either norepinephrine, a gold-standard vasopressor, and arginine vasopressin, a candidate alternative, are not well understood.Design-Randomized and controlled in vivo study. Setting-Research laboratory and animal facilities. Subjects-Adult rats treated with endotoxin (lipopolysaccharide) and/or vasopressors.Interventions-Rats were intraperitoneally injected with lipopolysaccharide (12 mg/kg) or saline and then infused with either saline, 0.375 μg/μL arginine vasopressin, or 32.5 μg/μL norepinephrine for 18 hrs. These vasopressor rates yielded respective targeted blood levels observed in human septic shock. Measurements and MainResults-Renal function, including glomerular filtration rate and fraction, renal blood flow, aquaporin-2, and arginine vasopressin-2 (V2 receptor) networking, water and salt handling, and urinary protein excretion, were evaluated. After lipopolysaccharide challenge arginine vasopressin infusion: 1) impaired creatinine clearance without affecting renal blood flow, glomerular filtration rate, and fraction but reduced free-water clearance, both of which being partially restored by the V2 receptor antagonist SR-121463B; 2) decreased the recognized ability of arginine vasopressin alone to recruit aquaporin-2 to the apical membrane increase its mRNA expression and urinary release; 3) increased urinary protein content but decreased specific kidney injury molecule-1, and Clara cell protein-16 release (p < 0.05 vs. lipopolysaccharide alone). Conversely, norepinephrine Severe sepsis is commonly associated with kidney dysfunction and accounts for >50% of intensive care unit admissions for acute renal failure (ARF) with a mortality rate of 75%, when compared with 45% in intensive care unit patients without sepsis (1,2). Septic shock can lead to altered renal blood flow (RBF) with afferent arteriolar vasoconstriction, resulting in ischemic kidneys, although this is still under debate. To compare outcomes, new RIFLE and AKIN criteria have been published as to acute kidney injury and ARF definitions, including creatinine, urine output (UO), and/or glomerular filtration rate (GFR) assessments (3,4). In parallel, hyperdynamic septic shock animal models have revealed increased RBF with a reduction in vascular resistance (5). Endotoxemia per se causes specific alterations in intra-RBF distribution, inducing an imbalance between "dilators" (nitric oxide, prostaglandins) and "constrictors" (endothelin, angiotensin II, norepinephrine [NE]) (5). NIH Public AccessSepsis treatment guidelines recommend the use of vasopressors in septic shock resistant to fluid resuscitation (i.e., sustained life-threatening low systemic blood pressure) (6). Indeed, infusion o...

Predialysis hypernatremia is a prognostic marker in acute kidney injury in need of renal replacement therapy

“…It did not assess the use of diuretics and antibiotics; sodium and free water content of infusions and diet were not informed. Diet protein content was not reported, although an overwhelming protein diet content in AKI and in sepsis may have trigged water and sodium reabsorption leading, according to experimental evidence, to an increase in urea transporters expression in the collecting ducts and to passive urea reabsorption [5]. The clinical observation of a significant increase in urea/ creatinine ratio in the hypernatremia categories in the present study may reflect these experimental data or even may represent an underresuscitation before ICU admission, in the hypernatremic group.…”

“…The predominance of sepsis diagnosis in hypernatremic patients has already been reported [15,35]. Sharshar et al [36] demonstrated that vasopressin deficiency develops in sepsis and contributes to water loss, and a vasopressin renal sensibility and aquaporin 2/V2 receptor dysfunction leading to an increased free water clearance and hypernatremia has been demonstrated in experimental sepsis [5].…”

“…In this setting, severe, mild, and even borderline dysnatremia have been associated with increased hospital mortality, regardless the severity of the underling disease [2][3][4]. Risk factors associated with dysnatremia in the ICU include hypotonic and hypertonic fluid infusions, diet, and medication sodium content, as well as acute kidney injury (AKI), patients' inaccessibility to water, and sepsis [5]. Darmon et al [3] reported AKI and the need of renal replacement therapy (RRT) at ICU admission as significant risk factors to dysnatremia.…”

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] . Thus, V2 receptor agonist activity appears to be involved in renal dysfunction of sepsis but the beneficial versus adverse mechanisms are incompletely elucidated.…”

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.…”