Ghrelin protects mice against endotoxemia-induced acute kidney injury

Wang W, Bansal S, Falk S, Ljubanovic D, Schrier R. Ghrelin protects mice against endotoxemia-induced acute kidney injury. Am J Physiol Renal Physiol 297: F1032-F1037, 2009. First published July 22, 2009; doi: 10.1152/ajprenal. 00044.2009.-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-alpha, IL-1 beta, 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-alpha 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 mu l/min, P < 0.001) and 24 h (147.2 +/- 20.3 vs. 59.4 +/- 20.7 mu l/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-alpha both in the circulation and kidney tissues. Thus, ghrelin may be a promising peptide in managing endotoxemia-induced AKI.