Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS

Abstract

Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis. We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible. Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression. LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver. Interestingly, impairment of renal function preceded iNOS activity by 30-60 min and occurred in tandem with decreased renal arginine production. The baseline rate of renal arginine production was approximately 60 micromol.h(-1).kg(-1), corresponding to an apparent plasma half-life of approximately 20 min, and decreased by one-half within 60 min of LPS. Calculations based on the systemic production and clearance show that normally only 5% of kidney arginine output is destined to become nitric oxide and that <25% of LPS-impaired renal production was converted to NOx in the first 4 h. In addition, we provide novel observations indicating that the kidney appears refractory to iNOS induction by LPS because no discernible enhancement of renal NOx production occurred within 4 h, and iNOS expression in the kidney was muted compared with that in liver or lung. These studies demonstrate that the major factor responsible for the rapid decrease in extracellular arginine content following LPS is impaired production by the kidney, a phenomenon that appears linked to reduced renal perfusion.

Acute renal response to LPS: impaired arginine production and inducible nitric oxide synthase activity

“…In previous studies, we showed that the LPS-induced changes in kidney arginine production occurred at a time and were of a sufficient magnitude to fully account for decreased plasma content (23). In fact, the production of arginine decreased before the expression of iNOS and therefore was clearly not mediated by NO.…”

“…Extracellular arginine primarily originates from the kidney, which, in turn, depends on the uptake and conversion of citrulline from plasma (7,8,(12)(13)(14)32). Estimates based on renal production and plasma concentration indicate that the turnover rate for extracellular arginine is ϳ40 min (23). Arginine is the precursor to nitric oxide (NO) via the action of at least three isoforms of nitric oxide synthase (NOS), and expression of the inducible isoform (iNOS) results in large-scale NO release (1).…”

A Rat Model of Early Sepsis: Relationships between Gentamicin Pharmacokinetics and Systemic and Renal Effects of Bacterial Lipopolysaccharide Combined with Interleukin-2

“…Other researchers have observed only a transient drop in the flow of urine collected from Wistar rats after a bolus dose of 1 mg/kg LPS, with a return to a baseline value by 150 min having also been observed. 22) The rate of urine flow was unaffected by a GE infusion rate of 0.05 mg/kg per min. Similar findings were made in Sprague Dawley rats after GE infusions at rates 5 to even 10 times higher.…”

“…21) Changes in renal function parameters observed in the early period following LPSIL-2 administration were comparable to those described by others after 1 mg/kg of LPS administered as an i.v. bolus 22) or 150 µg/kg per hour LPS given in a continuous i.v. infusion.…”

“…Higher doses induce systemic hypotension and a drop in GFR, whereas lower doses decrease GFR without major changes in blood pressure and associated multi-organ injury. 22,23) Low-dose IL-2 has been considered a mediator and enhancer of capillary leakage in early sepsis without immediate worsening of cardiovascular functions. 26) This results from a cascade of events leading to induction of NO synthesis and release which, directly or indirectly, injures capillaries and causes leakage.…”