Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal L-arginine deficiency

TY - JOUR

T1 - Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal L-arginine deficiency

AU - Betz, Boris

AU - Möller-Ehrlich, Kerstin

AU - Kress, Tobias

AU - Kniepert, Joachim

AU - Schwedhelm, Edzard

AU - Böger, Rainer H

AU - Wanner, Christoph

AU - Sauvant, Christoph

AU - Schneider, Reinhard

N1 - Copyright © 2013 Mosby, Inc. All rights reserved.

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

AB - 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.

KW - Acute Kidney Injury

KW - Amidohydrolases

KW - Animals

KW - Arginine

KW - Blotting, Western

KW - Chromatography, High Pressure Liquid

KW - Disease Models, Animal

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Intracellular Signaling Peptides and Proteins

KW - Kidney

KW - Kidney Function Tests

KW - Protein-Arginine N-Methyltransferases

KW - Rats

KW - Rats, Sprague-Dawley

KW - Real-Time Polymerase Chain Reaction

KW - Reperfusion Injury

KW - Tandem Mass Spectrometry

U2 - 10.1016/j.trsl.2013.04.005

DO - 10.1016/j.trsl.2013.04.005

M3 - SCORING: Journal article

C2 - 23707198

VL - 162

SP - 67

EP - 76

JO - TRANSL RES

JF - TRANSL RES

SN - 1931-5244

IS - 2

ER -