Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular
necrosis. This process has been demonstrated to be associated with reduced
nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that
L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile
saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal
injuries were linked to reduced NO production, L-Arg, a substrate for
NO synthase, was supplemented (5%) in
drinking water. Mice intoxicated with AA exhibited features of rapid-onset
acute kidney injury, including
polyuria, significantly increased plasma
creatinine concentrations,
proteinuria and fractional excretion of
sodium (P < 0.05), along with severe proximal tubular cell injury and increased
NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia,
polyuria,
proteinuria, fractional excreted
sodium and N-acetyl-β-D-
glucosaminidase enzymuria) and renal structure (tubular
necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of
reactive oxygen species and with an increase in
antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced
acute kidney injury by reducing oxidative stress and maintaining renal function.