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


METHODS
Randomized and controlled in vivo study.


METHODS
Research laboratory and animal facilities.


METHODS
Adult rats treated with endotoxin (lipopolysaccharide) and/or vasopressors.


METHODS
Rats were intraperitoneally injected with lipopolysaccharide (12 mg/kg) or saline and then infused with either saline, 0.375 microg/microL arginine vasopressin, or 32.5 microg/microL norepinephrine for 18 hrs. These vasopressor rates yielded respective targeted blood levels observed in human septic shock.


RESULTS
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 infusion did not add to lipopolysaccharide-induced alteration of urine biochemistry, except for improved creatinine clearance and increased microalbuminuria.


CONCLUSIONS
In this endotoxic model, dose-targeted arginine vasopressin infusion increased lipopolysaccharide-induced renal dysfunction without affecting renal blood flow and glomerular function, but with particular disruption of aquaporin-2/V2 receptor networking, consecutive decreased salt and water handling ability. This is in clear contrast with norepinephrine infusion and suggests specific arginine vasopressin-induced "tubular epithelial dysfunction."
Chagnon
Frederic
F
Groupe de Recherche en Physiopathologie Respiratoire, Centre de recherche clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
Vaidya
Vishal S
VS
Plante
Gerard E
GE
Bonventre
Joseph V
JV
Bernard
Alfred
A
Guindi
Chantal
C
Lesur
Olivier
O
D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2 / Q000032:analysis*; D001127:Arginine Vasopressin / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D011507:Proteinuria / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000032:analysis*; D012079:Renal Circulation / Q000502:physiology; D018805:Sepsis / Q000150:complications; D013141:Spiro Compounds / Q000494:pharmacology; D014598:Uteroglobin / Q000032:analysis; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D004731:Endotoxins; D008070:Lipopolysaccharides; D009025:Morpholines; D012333:RNA, Messenger; D017483:Receptors, Vasopressin; C556389:SCGB1A1 protein, human; D013141:Spiro Compounds; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D014598:Uteroglobin; C103281:satavaptan; D003404:Creatinine; D004837:Epinephrine