Urinary liver-type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone-induced acute kidney injury.

AIM: Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study. METHODS: Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram. RESULTS: The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased. CONCLUSION: Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

Urinary liver-type fatty acid binding protein is increased in the early stages of the disease with a risk of acute kidney injury induced by histone.

AIM: Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases. METHODS: Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava. RESULTS: After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP. CONCLUSIONS: Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.

Mechanism for exercise-mediated prevention against muscle wasting on extensor digitorum longus muscle in Spontaneously Diabetic Torii fatty rats.

We previously reported the significant increase in limb muscle strength and cross-sectional area of the type IIb muscle fibers in the extensor digitorum longus (EDL) muscle in a type 2 diabetic animal model, with Spontaneously Diabetic Torii (SDT) fatty rats (n = 6) undergoing regular treadmill exercise from 8 to 16 weeks of age compared with sedentary SDT fatty rats (n = 6). This study investigated the mechanism by which exercise training prevented skeletal muscle wasting in the EDL muscle of the SDT fatty rats. The endurance exercise for 8 weeks downregulated the expression of muscle RING-finger protein-1 (an E3 ubiquitin ligase) and upregulated the expression of CD31, insulin receptor substrate-2, and phosphorylated endothelial nitric oxide synthase in the EDL muscle of 16-week-old SDT fatty rats.Endurance exercise training might reduce muscle wasting by preventing muscle degradation and increasing the angiogenic response in the EDL muscle in type 2 diabetes.

Urinary L-Type Fatty Acid-Binding Protein Predicts Oxygen Demand of COVID-19 in Initially Mild Cases.

Early detection of illness trajectory in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients is crucial for patients and healthcare workers. An effective, noninvasive approach, with simple measurement for decision-making, is necessary in a pandemic to discriminate between high- and low-risk patients, even though both groups may exhibit mild symptoms in the beginning. OBJECTIVES: To predict COVID-19 disease severity within 10 days, distinguishing cases that will progress to moderate or severe versus mild, patient urinary L-type fatty acid-binding protein (L-FABP) was assayed within 4 days of receiving a diagnosis. The study also examined whether L-FABP point of care (POC) test is helpful in risk screening. DESIGN: Symptomatic subjects who tested positive for SARS-CoV-2 and were hospitalized were prospectively enrolled at the National Center for Global Health and Medicine (NCGM), Yamanashi Prefectural Central Hospital (YPCH), and Sinai Hospital in Maryland. The outcome of each case was evaluated 7 days after admission and the diagnostic performance of L-FABP was assessed. SETTING AND PARTICIPANTS: Subjects were treated for COVID-19 at public healthcare centers in Japan from January 31, 2020, to January 31, 2021, to NCGM, YPCH, and at Sinai Hospital in Baltimore, MD, during the same period. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine whether urinary L-FABP within 48 hours of admission can predict the patient's severity of COVID-19 1 week later. We obtained demographic data, information on clinical symptoms, radiographic images, and laboratory data. RESULTS: Diagnostic performance was assessed using receiver operating characteristic analysis. Of the 224 participants in the study, 173 initially had a mild form of COVID-19. The area under the curve (AUC) for a severe outcome was 93.5%. L-FABP POC risk prediction of a severe outcome had an AUC of 88.9%. CONCLUSIONS AND RELEVANCE: Urinary L-FABP can predict patient risk of COVID-19 illness severity. L-FABP POC is implementable for patient management. (ClinicalTrials.gov number, NCT04681040).

Angiotensin II type 1a receptor deficiency alleviates muscle atrophy after denervation.

The study aim was to determine if suppressed activation of angiotensin II type 1 receptor (AT1) prevents severe muscle atrophy after denervation. The sciatic nerves in right and left inferior limbs were cut in AT1a knockout homo (AT1a-/-) male mice and wild-type (AT1a+/+) male mice. Muscle weight and cross-sectional areas of type IIb muscle fibers in gastrocnemius muscle decreased at 7 and 21 days postdenervation in both AT1a-/- mice and AT1a+/+ mice, and the reduction was significantly attenuated in the denervated muscles of AT1a-/- mice compared to the AT1a+/+ mice. Gene expressions in the protein degradation system [two E3 ubiquitin ligases (muscle RING-finger protein-1 and Atrogin-1)] upregulated at 7 days postdenervation in all denervated mice were significantly lower in AT1a-/- mice than in AT1a+/+ mice. Activations of nuclear factor κB and Forkhead box subgroup O1, and protein expression of monocyte chemoattractant protein-1 were significantly suppressed in the AT1a-/- mice compared with those in the AT1a+/+ mice. In addition, suppressed apoptosis, lower infiltration of M1 macrophages, and higher infiltration of M2 macrophages were significantly observed at 21 days postdenervation in the AT1a-/- mice compared with those in the AT1a+/+ mice. In conclusion, the AT1 receptor deficiency retarded muscle atrophy after denervation.

Endurance Exercise Training-Attenuated Diabetic Kidney Disease with Muscle Weakness in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: The aim of this study was to evaluate protective effects of endurance exercise training against diabetic kidney disease (DKD) with muscle weakness by using male spontaneously diabetic Torii (SDT) fatty rats as type 2 diabetic animal models with obesity, hypertension, and hyperlipidemia. METHODS: Eight-week-old SDT fatty rats (n = 12) and Sprague-Dawley (SD) rats (n = 10) were randomly divided into exercise (Ex; SDT-Ex: n = 6, SD-Ex: n = 5) and sedentary groups (SDT-Cont: n = 6, SD-Cont: n = 5), respectively. Each group underwent regular treadmill exercise 4 times a week from ages 8-16 weeks. RESULTS: The exercise attenuated hypertension and hyperlipidemia and prevented increases in renal parameter levels without affecting blood glucose levels. In the SDT fatty rats, it prevented induction of renal morphological abnormalities in the interstitium of the superficial and intermediate layers of the cortex. Downregulated expression of endothelial nitric oxide synthase in the glomerulus of the SDT fatty rats was significantly upregulated by the exercise. The exercise upregulated the renal expressions of both medium-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor γ coactivator-1α related to fatty acid metabolism. It increased muscle strength and both muscle weight and cross-sectional area of type IIb muscle fibers in the extensor digitorum longus muscle in the SDT fatty rats. CONCLUSION: Endurance exercise training in type 2 diabetes ameliorates DKD by improving endothelial abnormality and enhancing fatty acid metabolism in addition to attenuated hypertension, hyperlipidemia, and muscle weakness independently of blood glucose levels.

Urinary liver-type fatty acid-binding protein in two dogs with acquired Fanconi syndrome: A case report.

Background: Fanconi syndrome (FS) is defined as multiple defects of the proximal tubules and is diagnosed by clinical symptoms. However, in dogs with FS, the damage in the proximal tubules that is responsible for the clinical symptoms has not been evaluated. Among FS cases, tubular damage in acquired FS is reversible following the elimination of a causative factor. Liver-type fatty acid-binding protein (L-FABP) is a biomarker of tubular damage in various animals including dogs. Urinary L-FABP measurement may be useful for the diagnosis and follow-up evaluation in canine FS. Case Description: At the first visit, two Toy Poodles that had no remarkable findings on physical examination presented with glycosuria without hyperglycemia, hypokalemia, hyperchloremia, increased levels of plasma alkaline phosphatase, and metabolic acidosis. Considering all the factors involved, the dogs were clinically diagnosed with acquired FS. The owner reported that they routinely fed the dog with chicken jerky, a recently considered cause of acquired FS. Following the withdrawal of the jerky, abnormalities including glycosuria improved in both dogs. Moreover, urinary L-FABP levels, which were high at diagnosis, presented a decreasing trend during the follow-up. However, in one dog, the elevated urinary L-FABP level did not return to normal. Conclusion: Although the clinical symptoms of acquired FS in dogs could be improved by the elimination of a causative factor, the severity of tubular damage described by urinary L-FABP may not be necessarily linked to the degree of functional deterioration. Therefore, the evaluation of proximal tubular damage by L-FABP may be of clinical value during the follow-up of acquired FS in canines.

Effect of GLP-1 receptor agonist, liraglutide, on muscle in spontaneously diabetic torii fatty rats.

This study investigated the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on skeletal muscles in rats with type 2 diabetes. Male SDT fatty rats (8-week-old) were provided liraglutide, or insulin-hydralazine for 8 weeks; control SDT fatty rats and SD rats were administered a vehicle. At 16 weeks of age, muscle strength of limbs was significantly lower in all SDT fatty rats compared to SD rats. While cross-sectional areas of type IIb muscle fibers in extensor digitorum longus muscle were significantly lower in SDT fatty rats than in SD rats, those of type I muscle fibers in soleus were similar in all rats. In the soleus of SDT fatty rats, liraglutide led to greater citrate synthase activity and cytochrome c oxidase subunit 5 B protein expression, independently of blood glucose and blood pressure levels. Liraglutide may contribute to preservation of mitochondrial content on soleus muscle in type 2 diabetes.

Effects of excessive sodium chloride loading in the spontaneously diabetic torii (SDT) fatty rats, a preclinical model of type 2 diabetes mellitus.

Type 2 diabetes mellitus represents an international health concern with its growing number of patients worldwide. At the same time, excessive salt consumption is also seen as a major cause of diseases such as hypertension and may expedite renal complications in diabetic patients. In this study, we investigated the effects of excessive sodium chloride supplementation on the kidney of the Spontaneously Diabetic Torii-Leprfa (SDT fatty) rat, an obese type 2 diabetes model. Male and female SDT fatty rats and normal Sprague-Dawley (SD) rats at 5 weeks of age were loaded with 0.3% sodium chloride (NaCl) in drinking water for 13 weeks. Blood serum and urinary parameters were observed throughout the experiment and kidney samples were examined in histopathological and genetical analyses. Significant changes on the body weight, blood pressure, urine volume, creatinine clearance, blood urea nitrogen (BUN), relative gene expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-ß (TGF-ß) were observed in the salt-loaded male SDT fatty rats. Urinary L-type fatty acid-binding protein (L-FABP) and albumin levels were higher observed in the salt-loaded male SDT fatty rats throughout the period, but urinary albumin levels in the female SDT fatty rats remain unchanged. In the kidney, slight Armani-Ebstein changes, tubular degeneration, hyaline cast, and inflammatory cell infiltration were observed in female SDT fatty rats while the levels of some changes were higher in the salt-loaded group. The kidney of the salt-loaded male SDT fatty rats demonstrated a higher degree of lesions compared to the female group and the male unloaded group. Histopathological changes in salt-loaded SDT fatty rats show that excessive salt consumption may act as a diabetic pathology exacerbation factor, but the pathology may be influenced by gender difference. Urinary L-FABP levels may act as a useful biomarker to detect slight tubular damages in the kidney. Excessive salt loading was shown to exacerbate the renal injury in SDT fatty rats.

Clinical evaluation of urinary liver-type fatty acid-binding protein for the diagnosis of renal diseases in dogs.

Liver-type fatty acid-binding protein (L-FABP) is a biomarker for the early detection of renal diseases in humans. L-FABP is a cytotoxic oxidation product secreted from the proximal tubules under ischemic and oxidative stress conditions. First, L-FABP gene expression in the kidney and liver was evaluated. Next, the urinary L-FABP concentrations in dogs with or without renal diseases were measured using a novel enzyme-linked immunosorbent assay kit. Urinary L-FABP was normalized relative to urinary creatinine (uCre) concentrations (µg/g uCre). Finally, the relationships between urinary L-FABP and renal biomarkers used in canine medicine or serum alanine transaminase (ALT) as an indicator of liver damage were examined. Serum and urine samples from 94 client-owned dogs including 23 dogs with renal diseases and 71 dogs without renal diseases were used for analysis. Relative L-FABP gene expression was confirmed both in the liver and kidney. Dogs with renal diseases had a significantly higher urinary L-FABP than those without, and its predictive cutoff value was 26 µg/g uCre. Urinary L-FABP was significantly correlated with serum creatinine (r=0.4674, P<0.01), urea nitrogen (r=0.4907, P<0.01), urine specific gravity (r=-0.5100, P<0.01), and urine protein/creatinine ratio (r=0.7216, P<0.01), but not with serum ALT. Hence, dogs with a high urinary L-FABP value were more likely to have renal diseases.

Preliminary study of urinary excretion of liver-type fatty acid-binding protein in a cat model of chronic kidney disease.

Urinary liver-type fatty acid-binding protein (uL-FABP) is a clinically useful biomarker for monitoring chronic kidney disease (CKD) in humans. However, long-term monitoring of uL-FABP in CKD cats has not been reported. The objective of this preliminary study was to investigate whether the urinary excretion of L-FABP could predict the deterioration of renal function in 2 CKD model cats. Urinary liver-type fatty acid-binding protein (uL-FABP) increased before standard renal biomarkers, including serum creatinine, blood urea nitrogen, and symmetric dimethylarginine, in 1 cat with deteriorating renal function, but remained low and relatively stable in another cat with stable renal function. Our results suggest that uL-FABP is a potential clinical biomarker for predicting the progression of CKD in cats, as it is in humans.

La protéine urinaire de liaison aux acides gras de type hépatique (uL-FABP) est un biomarqueur cliniquement utile pour la surveillance de l'insuffisance rénale chronique (MRC) chez l'homme. Cependant, aucune surveillance à long terme de l'uL-FABP chez les chats atteints d'IRC n'a été signalée. L'objectif de cette étude préliminaire était de déterminer si l'excrétion urinaire de L-FABP pouvait prédire la détérioration de la fonction rénale chez deux chats modèles de CKD. La protéine uL-FABP a augmenté avant les biomarqueurs rénaux standards, y compris la créatinine sérique, l'azote uréique sanguin et la diméthylarginine symétrique, chez un chat dont la fonction rénale se détériorait, mais est restée faible et relativement stable chez un autre chat dont la fonction rénale était stable. Nos résultats suggèrent que l'uL-FABP est un biomarqueur clinique potentiel pour prédire la progression de l'IRC chez le chat, comme c'est le cas chez l'homme.(Traduit par Docteur Serge Messier).

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion.

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a-/-) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a-/- and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a-/- mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a-/- mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a-/- mice. Acute tubular injury at 3 days postischemia was similar between the AT1a-/- mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a-/- mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.

Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats.

BACKGROUND: The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. METHODS: Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle. RESULTS: The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. CONCLUSIONS: Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Relationship between Urinary Liver-Type Fatty Acid-Binding Protein (L-FABP) and Sarcopenia in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: Type 2 diabetes (T2D) is a known risk factor for diabetic kidney disease (DKD) and sarcopenia in older patients. Because there may be an interaction between DKD and sarcopenia, the aim of the present study is to investigate the relationship between urinary levels of liver-type fatty acid-binding protein (L-FABP) and sarcopenia using a novel rat model of T2D. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats (n = 5) at 16 weeks of age were used as an animal model of T2D. Age- and sex-matched Sprague-Dawley (SD) rats (n = 7) were used as controls. Urine samples were obtained from the rats, and muscle strength was evaluated with the use of the forelimb grip test at 16, 20, and 24 weeks of age. Serum, kidney, soleus, and extensor digitorum longus (EDL) muscle samples were collected at 24 weeks of age. Urinary L-FABP levels were measured using dedicated enzyme-linked immunosorbent assays. RESULTS: Increased urinary L-FABP levels, focal glomerular sclerosis, moderate interstitial inflammation and fibrosis, and accumulation of renal oxidative proteins were significantly observed in the SDT fatty rats, compared to the SD rats. Muscle weight, muscle strength, cross-sectional areas of both type I and type IIb muscle fibers, and increasing rate of muscle strength were significantly decreased in the SDT fatty rats compared to the SD rats at 24 weeks. Urinary L-FABP levels at 20 and 24 weeks were significantly negatively correlated with muscle strength. Urinary L-FABP levels at 16 weeks were significantly negatively correlated with the increasing rate of muscle strength. CONCLUSIONS: Urinary L-FABP reflects the degree of muscle strength and weight, as well as cross-sectional areas of muscle fibers. Although further clinical study is needed, urinary L-FABP may be useful to monitor the progression of sarcopenia and DKD in T2D patients.

Renal expression and urinary excretion of liver-type fatty acid-binding protein in cats with renal disease.

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) is a biomarker for early detection of renal disease in humans. Liver-type fatty acid-binding protein is cytotoxic oxidation products secreted from proximal tubules under ischemia and oxidative stress. OBJECTIVE: To examine renal expression and quantify urinary excretion of L-FABP in catswith renal disease. ANIMALS: One hundred and thirty-four client-owned cats including 34 cats with serum creatinine (sCre) values >1.6 mg/dL and 10 other cats that died in clinics. METHODS: Tissue expressions of L-FABP were examined by reverse transcription polymerase chain reaction and Western blotting. Urinary L-FABP (uL-FABP) and serum L-FABP (sL-FABP) levels were determined by enzyme-linked immunosorbent assay. Anti-liver-type fatty acid-binding protein antibody immunostained renal sections. RESULTS: Feline kidneys express L-FABP. Strong L-FABP signals were observed in the lumens of proximal tubular cells in 5 cats with high uL-FABP excretion, but not in 5 cats with low uL-FABP excretion. In 9 normal cats, uL-FABP index was <1.2 µg/g urinary creatinine (uCre). High uL-FABP indexes (>10.0 µg/g uCre) were detected in 7 of 100 cats with low sCre (<1.6 mg/dL) and 18 of 44 cats with high sCre (>1.6 mg/dL). There was a weak correlation between L-FABP index and sCre, serum symmetric dimethylarginine (SDMA), or blood urea nitrogen (BUN), and these correlation coefficients were increased by analyzing only data of cats with sCre >1.6 mg/dL. There was a weak correlation between u L-FABP index and sL-FABP in all tested cats, but not in cats with high sCre. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates correlations between L-FABP and current renal biomarkers for chronic kidney disease in cats, such as sCre and SDMA. Liver-type fatty acid-binding protein may be a potential biomarker to predict early pathophysiological events in feline kidneys.

The Possibility of Urinary Liver-Type Fatty Acid-Binding Protein as a Biomarker of Renal Hypoxia in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. OBJECTIVE: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. RESULTS: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. CONCLUSIONS: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

Temporal changes in urinary excretion of liver-type fatty acid binding protein (L-FABP) in acute kidney injury model of domestic cats: a preliminary study.

Liver-type fatty acid-binding protein (L-FABP) is a biomarker for the early detection of renal diseases in humans. It is secreted along with cytotoxic oxidation products from proximal tubular epithelial cells under conditions of ischemia and/or oxidative stress. This study examined urinary L-FABP excretion under renal ischemia in feline acute kidney injury (AKI) model. L-FABP excretion increased immediately after renal ischemia/reperfusion, despite the absence of obvious structural damage to the kidneys, in the two AKI model cats studied. L-FABP was detected in the renal tubular lumen immediately after renal ischemia/reperfusion in the two cats, but not in a sham surgery cat. These results suggested that high L-FABP excretion is a pathophysiological response associated with antioxidant defense in proximal tubules with renal ischemia and/or oxidative stress in a feline model.

Renoprotective effects of voluntary running exercise training on aldosterone-induced renal injury in human L-FABP chromosomal transgenic mice.

Tubulointerstitial damage is a crucial therapeutic target in preventing chronic kidney disease (CKD) progression. Inappropriately activated renin-angiotensin-aldosterone system (RAAS) in the tubulointerstitial area is strongly associated with tubulointerstitial damage progression. Therefore, this study aimed to determine whether there is a beneficial effect of voluntary running exercise training on aldosterone-induced renal injury. Human L-type fatty acid-binding protein (L-FABP) chromosomal transgenic (L-FABP+/-) male mice were used to evaluate the effect of exercise by using urinary L-FABP, a tubular marker. The mice were assigned to either the exercise group that performed voluntary running exercise training using a running wheel or the control group. Subsequently, two groups were injected with aldosterone (0.125 µg kg-1 min-1) and administered 1% NaCl water, and two groups were administered aldosterone only in solvent 4 weeks after initiating the exercise. Aldosterone was injected for another 4 weeks, and NaCl water was administered from 5 weeks after starting the exercise until 8 weeks. Although both aldosterone and NaCl water significantly decreased the running distance, tubulointerstitial damage involving interstitial infiltration of macrophages and fibrosis and the elevation of urinary human L-FABP induced by aldosterone injection was prevented by voluntary running exercise training. Urinary human L-FABP levels were significantly correlated with the degree of tubulointerstitial damage. In conclusion, voluntary running exercise training delayed tubulointerstitial damage progression in the aldosterone-induced renal injury model and therefore may be a promising nonpharmacological strategy in CKD.

Serum Liver-Type Fatty Acid-Binding Protein Is a Possible Prognostic Factor in Human Chronic Liver Diseases From Chronic Hepatitis to Liver Cirrhosis and Hepatocellular Carcinoma.

Liver-type fatty acid-binding protein (L-FABP) is a key regulator of fatty acid metabolism, but serum L-FABP levels are not well investigated in chronic liver diseases. We aimed to elucidate the prognostic ability of serum L-FABP in human chronic liver diseases and compare it with the albumin-bilirubin (ALBI) score. In 242 chronic liver disease patients, including chronic hepatitis (CH, n = 100), liver cirrhosis (LC, n = 142), and presence of hepatocellular carcinoma (HCC, n = 144), serum L-FABP levels were correlated with liver function (P < 0.0001), increased in LC compared with CH (P < 0.01), and correlated to ALBI score (P < 0.0001). Serum L-FABP levels were increased in the presence of HCC (P < 0.0001), correlating to des-gamma-carboxy prothrombin (P < 0.0001), alpha-fetoprotein (P = 0.009), and Barcelona-Clinic Liver Cancer stage. In the average follow-up period of 1,054 days, serum L-FABP levels were elevated (P < 0.0001) in patients who eventually died. The area under the curve (AUC) of serum L-FABP (0.764) was higher than that of ALB (0.709), and the patients with serum L-FABP ≤ 6.8 ng/mL had significantly longer rates of survival (P < 0.0001). Serum L-FABP (hazard ratio [HR] 4.0; P < 0.001), HCC (HR 3.7; P = 0.001), ALBI score (HR 2.7; P < 0.001), and age (HR 1.0; P = 0.049) were independent predictors of survival. In the subgroup who maintained liver function, the AUC of serum L-FABP (0.751) was higher than that of ALB (0.643). In this subgroup, serum L-FABP (HR 4.4; P = 0.002) and HCC (HR 13.9; P < 0.001) were independent predictors of survival. Conclusion: Serum L-FABP is a possible predictor of survival in chronic liver diseases from CH to LC and HCC, including any subgroup that maintains liver function.

Urinary Level of Liver-Type Fatty Acid Binding Protein Reflects the Degree of Tubulointerstitial Damage in Polycystic Kidney Disease.

BACKGROUND/AIMS: Polycystic kidney disease (PKD) is a common, progressive, and heritable type of kidney disease. Although certain imaging modalities are useful for the diagnosis and staging of PKD, they cannot adequately monitor the severity of interstitial inflammation and fibrosis. Therefore, the present study evaluated the urinary level of liver-type fatty acid binding protein (L-FABP) as a marker of interstitial inflammation and fibrosis in PKD. METHODS: Male PCK/CrljCrl-Pkhd1pck/Crl (PCK) rats (n = 34) were used as an animal model of the PKD. Age-and sex-matched Sprague-Dawley rats (SD) (n = 34) were used as controls. Urine samples were obtained from the rats at 8, 12, 16, 20, and 24 weeks of age, and the sera and kidney tissues were obtained at 8, 16, 20, and 24 weeks of age. RESULTS: All PCK rats developed cysts, and the degrees of tubular epithelial cell proliferation and interstitial inflammation increased linearly with age in these model rats relative to the controls. Interstitial fibrosis tended to increase in the PCK rats from 8 to 20 weeks of age, and revealed a peak level at 20 weeks. The urinary L-FABP levels increased linearly with age in the PCK rats, and the levels at 12, 16, 20, and 24 weeks were significantly higher than those in the controls. The urinary levels of L-FABP in the PCK rats correlated significantly with the severity of tubulointerstitial damage; specifically, we observed a significant correlation of the urinary levels at 16 weeks of age with the total kidney volume at 20 weeks. In contrast, both PCK and SD rats exhibited similar serum levels of L-FABP. CONCLUSION: Urinary L-FABP reflects the progression of tubulointerstitial damage, and therefore, may be a useful marker for monitoring the progression of PKD.