Urinary Excretion of Fatty Acid-Binding Protein Reflects Stress Overload on the Proximal Tubules

Kamijo, Aki; Sugaya, Takeshi; Hikawa, Akihisa; Okada, Mitsuhiro; Okumura, Fumikazu; Yamanouchi, Masaya; Honda, Akira; Okabe, Masaru; Fujino, Tomoya; Hirata, Yasunobu; Omata, Masao; Kaneko, Ritsuko; Fujii, Hiroshi; Fukamizu, Akiyoshi; Kimura, Kenjiro

doi:10.1016/s0002-9440(10)63384-6

Cited by 205 publications

(234 citation statements)

References 44 publications

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“…These results are consistent with previous studies (4,5) in patients with nondiabetic glomerular diseases, in which urinary L-FABP was associated with severity of tubulointerstitial injury, proteinuria, and the rate of progression of kidney disease. These findings may implicate a common mechanism of increased urinary L-FABP excretion in the pathogenesis of diabetic and nondiabetic kidney diseases.…”

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confidence: 93%

Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Patients With Diabetic Nephropathy

et al. 2005

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T ubulointerstitial damage plays a crucial role in the progression of kidney diseases, including diabetic nephropathy (1). Among several distinct types of fatty acid-binding protein (FABP), liver-type FABP (L-FABP) is abundantly expressed in hepatocytes and constitutively expressed in proximal tubular cells of the kidney (2). L-FABP incorporates albumin-bound free fatty acids (FFAs) that are filtered through the glomeruli into proximal tubular cells and transports FFAs from the cytosol to the nucleus (3). In transgenic mice expressing human L-FAPB, protein overload, res u l t i n g i n m a s s i v e p r o t e i n u r i a , upregulated renal L-FABP expression and increased its urinary excretion (4), suggesting that urinary L-FABP may reflect tubulointerstitial damage. Recently, in patients with nondiabetic glomerular disease, urinary excretion of L-FABP increased in parallel with the severity of tubulointerstitial injury and correlated with proteinuria and the rate of progression of renal disease, suggesting that L-FABP may be a useful indicator for the progression of nondiabetic kidney disease (4,5). To determine the clinical significance of L-FABP in patients with diabetic nephropathy, we conducted a crosssectional study comparing urinary L-FABP excretion in diabetic patients with serial stages of kidney disease. RESEARCH DESIGN ANDMETHODS -Adult patients with type 2 diabetes were recruited from the outpatient clinic of the Division of Nephrology and Hypertension, Diabetes Center, Tokyo Women's Medical University Hospital, Tokyo, Japan. Patients were classified into four stages of nephropathy according to albumin-to-creatinine ratio (ACR) in the first-morning urine and serum creatinine concentrations. Patients with a serum creatinine concentration Ն2.0 mg/dl were categorized as having renal failure. Patients with serum creatinine Ͻ2.0 mg/dl were classified as normoalbuminuric if ACR was Ͻ30 mg/g creatinine, as microalbuminuric if ACR was 30 -299 mg/g creatinine, and as having clinical albuminuria if ACR was Ն300 mg/g creatinine (6).Urinary albumin and L-FABP concentrations were measured by the latex agglutination method (5) and a highly sensitive sandwich enzyme-linked immunosorbent assay (CMIC, Tokyo, Japan). Concentrations were normalized for urine creatinine concentration. Intra-and interassay coefficients of variation for the urine L-FABP concentration were 7.0 -21.7 and 1.2-7.4%, respectively. The detection limit of L-FABP was 0.15 ng/ml; concentrations below this limit were defined as 0.10 ng/ml. Glomerular filtration rate (GFR) was estimated using the abbreviated equation proposed by the MDRD (Modification of Diet in Renal Disease) study group (7).Data were expressed as arithmetic mean Ϯ SD or geometric mean (95% CI), as appropriate according to data distribution. Continuous data were compared using one-way ANOVA followed by multiple comparisons by Tukey's Studentized range test; categorical data were analyzed with Cochran-Armitage trend test. For univariate correlation analyses, Spearman's correlation c...

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confidence: 93%

Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Patients With Diabetic Nephropathy

et al. 2005

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“…It might be possible that one or more receptors and transporters contributing to reabsorption of LMWPs and albumin were affected by testosterone, and their excretion levels had varied. In terms of L-FABP, stress such as urinary protein overload led to increase in urinary L-FABP excretion level (Kamijo et al, 2004). Higher urinary excretion level of total protein in the intact and sham-operated male rats compared to intact female rats and orchidectomized male rats, respectively, could be one of the factors which increase in urinary L-FABP excretion level (Fig.…”

Section: Discussionmentioning

confidence: 96%

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

et al. 2017

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-Urinary biomarkers have been used widely in preclinical toxicity studies to detect dysfunctions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on urinary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excretion levels of leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and β2-microglobulin (β2-MG), and lower excretion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, γGTP, N-acetyl-β-D-glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, β2-MG and neutrophil gelatinaseassociated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excretion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, γGTP, total protein, L-FABP, Cys-C, and β2-MG, may closely relate to the endogenous testosterone.

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“…27 Briefly, genomic DNA of human L-FABP, including its promoter region (13 kb), was microinjected into fertilized eggs obtained from C57Bl/6 and CBA mice; ICR mice were used as transfected-egg recipients. The resultant transgenic mice were backcrossed for more than nine generations onto C57Bl/6 mice to obtain homozygous mutant mice with an inbred background.…”

Section: H-l-fabp-tg Mice and The Renal I/r Modelmentioning

confidence: 99%

Renal L-Type Fatty Acid–Binding Protein in Acute Ischemic Injury

Yamamoto

Noiri

Ono

et al. 2007

Journal of the American Society of Nephrology

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Fatty acid-binding proteins (FABPs) bind unsaturated fatty acids and lipid peroxidation products during tissue injury from hypoxia. We evaluated the potential role of L-type FABP (L-FABP) as a biomarker of renal ischemia in both human kidney transplant patients and animal models. Urinary L-FABP levels were measured in the first urine produced from 12 living-related kidney transplant patients immediately after reperfusion of their transplanted organs, and intravital video analysis of peritubular capillary blood flow was performed simultaneously. A significant direct correlation was found between urinary L-FABP level and both peritubular capillary blood flow and the ischemic time of the transplanted kidney (both P Ͻ 0.0001), as well as hospital stay (P Ͻ 0.05). In human-L-FABP transgenic mice subjected to ischemiareperfusion injury, immunohistological analyses demonstrated the transition of L-FABP from the cytoplasm of proximal tubular cells to the tubular lumen. In addition, after injury, these transgenic mice demonstrated lower blood urea nitrogen levels and less histological injury than injured wild-type mice, likely due to a reduction of tissue hypoxia. In vitro experiments using a stable cell line of mouse proximal tubule cells transfected with h-L-FABP cDNA showed reduction of oxidative stress during hypoxia compared to untransfected cells. Taken together, these data show that increased urinary L-FABP after ischemic-reperfusion injury may find future use as a biomarker of acute ischemic injury.

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Urinary Excretion of Fatty Acid-Binding Protein Reflects Stress Overload on the Proximal Tubules

Abstract: Urinary excretion of human liver-type fatty acid-binding protein (hL-FABP

Cited by 205 publications

References 44 publications

Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Patients With Diabetic Nephropathy

Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Patients With Diabetic Nephropathy

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

Renal L-Type Fatty Acid–Binding Protein in Acute Ischemic Injury

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