ENDOTOXEMIA EXACERBATES KIDNEY INJURY AND INCREASES ASYMMETRIC DIMETHYLARGININE IN YOUNG BILE DUCT-LIGATED RATS

Cirrhosis increases the risk of kidney injury and sepsis, leading to increased mortality. Elevated levels of plasma asymmetric dimethylarginine (ADMA) occur in patients critically ill with cirrhosis, renal failure, and sepsis. We used a rat model of cirrhosis with superimposed sepsis to assess the relationship of plasma and tissue ADMA profiles with acute kidney injury and survival. Seventeen-day-old male Sprague-Dawley rats (n = 37) were randomly assigned to four groups: (1) sham operation plus diet control (n = 6); (2) bile duct ligation (BDL, n = 8); (3) sham operation plus lipopolysaccharide (LPS, n = 9); and (4) BDL plus LPS (n = 14). Lipopolysaccharide was given by intraperitoneal injection (1 mg/kg in saline) 3 h before sacrifice. All rats were sacrificed 14 days after surgery. Lipopolysaccharide increased the rate of BDL-associated death and dysfunction of the liver and kidneys. These results were supported by increased levels of plasma ADMA and a decreased L-arginine/ADMA ratio (AAR). Plasma and tissue levels of ADMA and AAR were not correlated. Lipopolysaccharide restored BDL-induced ADMA level elevation in the liver but increased ADMA level in the kidneys. Lipopolysaccharide increased hepatic AAR, decreased renal AAR, and paradoxically mediated the expression of neuronal nitric oxide synthase-beta in the liver and kidneys. A novel mechanism underlies the LPS-mediated L-arginine-ADMA-nitric oxide pathway activation and exacerbation of kidney injury and mortality in our BDL model. In the presence of cirrhosis with superimposed sepsis, simultaneous lowering of ADMA levels and enhancement of L-arginine levels to restore plasma and renal AARs may be an optimal strategy for the treatment of kidney injury.