Availability of
L-arginine, the exclusive substrate for
nitric oxide synthases, plays an important role in kidney
ischemia/reperfusion injury. The endogenous
L-arginine derivatives asymmetrical
dimethylarginine (ADMA) and symmetrical
dimethylarginine (SDMA) block cellular
L-arginine uptake competitively, thereby inhibiting the production of
nitric oxide. ADMA also blocks
nitric oxide synthase activity directly. Here, we investigate the pathomechanistic impact of ADMA and SDMA on ischemic
acute kidney injury. Rats were subject to bilateral renal
ischemia (60 minutes)/reperfusion (24 hours) injury. Impairment of renal function was determined with
inulin clearance (glomerular filtration rate) and para-aminohippurate (PAH) clearance (renal plasma flow).
L-arginine, ADMA, and SDMA levels were measured by liquid chromatography-tandem mass spectrometry.
L-arginine was extracted from renal tissue and analyzed by
enzyme-linked
immunosorbent assay, and
protein and
messenger RNA expressions were determined by Western blot and real-time reverse transcription polymerase chain reaction. Renal function deteriorated severely after
ischemia/reperfusion injury, as demonstrated by
inulin and PAH clearance. Serum ADMA and SDMA increased, but tissue expression of specific ADMA or SDMA synthesizing and metabolizing
enzymes (
protein arginine methyltransferases and dimethyl
arginine dimethylaminohydrolases) did not alter. Serum
L-arginine increased as well, whereas intracellular
L-arginine concentration diminished. Renal
messenger RNA expression of
cationic amino acid transporters, which mediate
L-arginine uptake, remained unchanged. In serum, the ratio of
L-arginine to ADMA did not alter after
ischemia/reperfusion injury, whereas the ratios of
L-arginine to SDMA and ADMA to SDMA decreased. A marked increase in serum SDMA, especially when accompanied by a diminished
L-arginine-to-SDMA ratio, might reflect competitive inhibition of cellular
L-arginine uptake by SDMA. As a consequence, a pathologic renal
L-arginine deficiency in ischemic
acute kidney injury results.