Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: a trial of separate evaluation of reabsorption.
OBJECTIVE
Fanconi syndrome is a renal dysfunction characterized by various combinations of renal tubular transport dysfunction involving amino acids, glucose, protein and other substances. Most reabsorption of amino acids occurs in proximal renal tubule segment 1 (S1). The present study evaluated the possibility of early detection of drug-induced Fanconi syndrome, based on decreased renal accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine (125I-IMT), an amino acid transport marker, in the S1 region of renal cortex. The present experimental model used maleate (MAL)-induced Fanconi syndrome in mice. Results were compared between 125I-IMT and 3 other clinical renal radiopharmaceuticals: 99mTc-2,3-dimercaptosuccinic acid (99mTc-DMSA); 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3); and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA).


METHODS
Male ddY mice (age, 6 weeks; body weight, 25 g) were used to create a Fanconi model of renal dysfunction. A single dose of maleate disodium salt was administered by intraperitoneal injection (6 mmol/kg). Hematoxylin and eosin (HE) staining of the renal cortex, renal autoradiography and measurement of renal radioactivity of labeled compounds were performed at 30, 60, 90 and 120 min after MAL injection. At 5 min after injection of labeled compounds (18.5 kBq for accumulation experiment, 670 kBq for autoradiography), animals were sacrificed by ether overdose and kidneys were removed. For the accumulation experiment, radioactivity was measured using a well-type scintillation counter. For autoradiography, 20-microm sections of frozen kidney were used with Bio-Imaging Analyzer.


RESULTS
At 30 min after MAL injection, HE staining showed pyknosis in some proximal tubule cells. At that time, accumulations of 125I-IMT and 99mTc-DMSA in the S1 region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of 99mTc-DTPA in the S1 region, but had no effect on accumulation of 99mTc-MAG3 in the S 1 region.


CONCLUSIONS
Decreased accumulation of 123I-IMT in the S1 region appears to represent a useful marker for detection of MAL-induced Fanconi syndrome. In future, we plan to assess the efficacy of using 125I-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.
Shikano
Naoto
N
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan. sikano@ipu.ac.jp
Nakajima
Syuichi
S
Kotani
Takashi
T
Itoh
Yusuke
Y
Nishii
Ryuichi
R
Yoshimoto
Mitsuyoshi
M
Flores
Leo Garcia
LG
Saji
Hideo
H
Ishikawa
Nobuyoshi
N
Kawai
Keiichi
K
D000042:Absorption; D000818:Animals; D004195:Disease Models, Animal; D005198:Fanconi Syndrome / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism*; D007672:Kidney Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008298:Maleates; D008657:Metabolic Clearance Rate; D008781:Methyltyrosines / Q000493:pharmacokinetics*; D051379:Mice; D008815:Mice, Inbred Strains; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution
D008298:Maleates; D008781:Methyltyrosines; D019275:Radiopharmaceuticals; C030272:maleic acid; C030855:3-iodo-alpha-methyltyrosine