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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/F1032    most recent 00044.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, W. Articles by Schrier, R. PubMed PubMed Citation Articles by Wang, W. Articles by Schrier, R.

Ghrelin protects mice against endotoxemia-induced acute kidney injury

¹Department of Medicine, University of Colorado Denver, Aurora, Colorado; and ; ²Department of Pathology, Dubrava University Hospital, Zagreb, Croatia

Submitted January 26, 2009 ; accepted in final form July 21, 2009

Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50–80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI. Studies were conducted in a normotensive endotoxemia-induced AKI model in mice by intraperitoneal injection of 3.5 mg/kg LPS. Serum ghrelin levels were increased during endotoxemia accompanied by increased ghrelin receptor (GHSR-1a) protein expression in the kidney. Ghrelin administration (1.0 mg/kg sc 6 h and 30 min before and 14 h after LPS) significantly decreased serum cytokine levels (TNF-, IL-1β, and IL-6) and serum endothelin-1 levels which had been induced by LPS. The elevated serum nitric oxide (NO) levels and renal inducible NO synthase expression were also decreased by ghrelin. Renal TNF- levels were also increased significantly in response to LPS and ghrelin significantly attenuated this increase. When administrated before LPS, ghrelin protected against the fall in glomerular filtration rate at 16 h (172.9 ± 14.7 vs. 90.6 ± 15.2 µl/min, P < 0.001) and 24 h (147.2 ± 20.3 vs. 59.4 ± 20.7 µl/min, P < 0.05) as well as renal blood flow at 16 h (1.65 ± 0.07 vs. 1.47 ± 0.04 ml/min, P < 0.01) and 24 h (1.56 ± 0.08 vs. 1.22 ± 0.03 ml/min, P < 0.05) after LPS administration without affecting mean arterial pressure. Ghrelin remained renal protective even when it was given after LPS. In summary, ghrelin offered significant protection against endotoxemia-induced AKI. The renal protective effect of ghrelin was associated with an inhibition of the proinflammatory cytokines. Of particular importance was the suppression of TNF- both in the circulation and kidney tissues. Thus, ghrelin may be a promising peptide in managing endotoxemia-induced AKI.

sepsis; proinflammatory cytokines