Rapid and segmental specific dysregulation of AQP2, S256-pAQP2 and renal sodium transporters in rats with LPS-induced endotoxaemia

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2009-08, Vol.24 (8), p.2338-2349
• Main Authors: Olesen, Emma T. B., de Seigneux, Sophie, Wang, Guixian, Lütken, Sophie C., Frøkiær, Jørgen, Kwon, Tae-Hwan, Nielsen, Søren
• Format: Article
• Language: English
• Subjects: acute renal failure; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; aquaporin; Aquaporin 2 - metabolism; Biological and medical sciences; Blotting, Western; Down-Regulation; Emergency and intensive care: renal failure. Dialysis management; Endotoxemia - chemically induced; Endotoxemia - metabolism; Endotoxemia - pathology; Enzyme Inhibitors - pharmacology; Immunoblotting; Immunoenzyme Techniques; iNOS; Intensive care medicine; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Lipopolysaccharides - pharmacology; LPS; Lysine - analogs & derivatives; Lysine - pharmacology; Macrophages - metabolism; Male; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Phosphorylation - drug effects; Rats; Rats, Wistar; Renal failure; Sodium - urine; Sodium-Potassium-Chloride Symporters - metabolism; Solute Carrier Family 12, Member 1; urine concentration
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfp011

Background. Acute renal failure (ARF) is a frequent complication of sepsis. Characteristics of ARF in sepsis are impaired urinary concentration, increased natriuresis and decreased glomerular filtration rate (GFR), in which inducible nitric oxide synthase (iNOS) has been revealed to play a role. Aims. We aimed to investigate renal water and sodium excretion and in parallel the segmental regulation of renal AQP2 and major sodium transporters in rats with acute LPS-induced endotoxaemia. Next, we aimed to examine the changes of iNOS expression and activated macrophage infiltration in the kidney and the effects of iNOS inhibition on AQP2 and NKCC2 expression in LPS rats. Methods. Rats were treated with LPS (i.p.) or with LPS + iNOS inhibitor L-NIL, and 6 h later kidneys were subjected to semiquantitative immunoblotting and immunohistochemistry. Results. Polyuria and increased natriuresis were seen 6 h after LPS injection alongside downregulation of both AQP2 and S256-phosphorylated AQP2 in CTX/OSOM and ISOM but not in inner medulla (IM). Thick ascending limb sodium transporters NHE3 and NKCC2 were downregulated in ISOM and NaPi2 was decreased in CTX/OSOM, whereas NCC and ENaC were not consistently downregulated. Immunolabelling intensity of iNOS was increased in vascular structures and transitional epithelium, and an infiltration of activated macrophages was seen in CTX and ISOM. L-NIL co-treatment prevented the downregulation of NKCC2 but not AQP2 in LPS rats. Conclusions. Early downregulation of AQP2 and sodium transporters takes place segmentally in the kidney after LPS administration. In addition, an infiltration of activated macrophages and increased iNOS expression may play a role in the urinary concentrating defect in acute LPS-induced entotoxaemia.