Tomohisa Yamashita

Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation.

Background Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. Methods We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic–euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH+ and FH–, respectively; n = 15 each). Results Serum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH+ group had a significantly lower level of M value and higher level of FABP4 than did the FH– group, and FABP4 concentration was an independent determinant of the M value. Conclusions FABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension.

Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy

Although diabetic nephropathy (DN) is a major cause of end‐stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin‐producing bone marrow‐derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)‐α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP‐Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high‐fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF‐α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ‐diabetic mice, 8.6% in HFD‐diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF‐α and caspase‐3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.—Yamashita, T. Fujimiya, M., Nagaishi, K., Ataka, K., Tanaka, M., Yoshida, H., Tsuchihashi, K., Shimamoto, K., Miura, T. Fusion of bone marrow‐derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy. FASEB J. 26, 1559‐1568 (2012). www.fasebj.org

The impact of elevation of serum uric acid level on the natural history of glomerular filtration rate (GFR) and its sex difference

BACKGROUND The impact of elevation of the serum uric acid level (SUA) on the natural history of glomerular filtration rate (GFR) remains controversial. METHODS If elevation of SUA is a result, rather than a cause, of a decline in GFR, the relationship between SUA and GFR should be the same in the same population over years except for shifts by age-dependent reduction of GFR. We tested this hypothesis using data from two cohorts and a group of allopurinol-treated patients. RESULTS In Cohort 1 consisting of urban residents aged 40.6 ± 9.0 years (n = 3 446), SUA was inversely correlated with estimated GFR (eGFR) in both men and women, and the slope of the SUA-eGFR relationship was steeper in women than in men. The slopes of the regression lines became significantly steeper after a 6-year interval in both sexes, and the change in the slope was larger in women. A similar sex difference in the SUA-eGFR relationship and 6-year change in the slope were observed in Cohort 2 consisting of rural town residents aged 61.7 ± 12.2 years (n = 404). Multiple regression analyses showed that explanatory factors of eGFR after a 6-year interval were age and SUA at baseline in both cohorts, and partial regression coefficients of SUA were more negative in women than in men. The SUA-eGFR relationship in allopurinol-treated patients (n = 346, 63.5 ± 13.3 years old) was similar to that in Cohort 2. CONCLUSIONS The results indicate that elevation of SUA accelerates the yearly decline in eGFR and that women are more susceptible to urate-induced decline in eGFR.

Bone Marrow Stem Cell Abnormality and Diabetic Complications

Long‐lasting diabetes impairs the function of multiple organs, which consists of degeneration of various tissues with increasing apoptosis of target cells. Recently, we found that hyperglycemia induced the appearance of abnormal cells in the bone marrow and cell fusion between bone marrow‐derived cells and hepatocytes, peripheral neural cells, or renal tubular cells occurred in diabetic animals. Fused cells in these organs expressed TNFα, and accelerated apoptosis, suggesting that these events might be a cause of diabetic complications. In this review, we propose a new concept that bone marrow stem cell abnormality causes diabetic complications, and this concept might provide new strategies for treatment of diabetes‐associated tissue damage. Anat Rec, 2012.

A Case of Crescentic Glomerulonephritis Complicated with Hypocomplementemic Urticarial Vasculitis Syndrome and ANCA-Associated Vasculitis

Systemic urticaria in a 64-year-old woman was diagnosed as leukocytoclastic vasculitis by a punch biopsy of the skin. Her physical findings improved after prescription of prednisolone at a dose of 20 mg/day, but the skin rash relapsed with renal dysfunction, proteinuria, and hematuria when the dose of prednisolone was reduced over a period of 9 months to 1 mg/day. She was admitted to our institute for further examination, when urinary protein and plasma creatinine levels were 0.8 g/day and 1.7 mg/dL, respectively. Complement analysis showed that levels of total hemolytic component, component C3 fraction, and component C4 fraction were 30∼60% of normal values and the titer of anti-neutrophil cytoplasmic antibody for myeloperoxidase (MPO-ANCA) was 89 EU (normal range, <10 EU), though there were no immunologic disorders such as systemic lupus erythematosus. Cellular crescentic glomerulonephritis was observed by light microscopy, and immunofluorescent studies showed positive staining for IgG, IgM, C3, C4, and C1q. Electron microscopy showed mesangial and subendothelial deposits with circumferential mesangial interposition. She fulfilled the diagnostic criteria for hypocomplementemic urticarial vasculitis syndrome (HUV), and ANCA-associated vasculitis (AAV) was also indicated by small vessel vasculitis and positive MPO-ANCA. Steroid pulse therapy with methylprednisolone followed by oral prednisolone improved her general condition and hypocomplementemia, and MPO-ANCA became negative. HUV and AAV are distinct clinical disorders, though both affect small blood vessels. Here we report a case of AAV-complicated HUV with crescentic glomerulonephritis.

Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal toll-like receptors in rats.

Acute kidney injury (AKI) after acute myocardial infarction (MI) worsens the prognosis of MI patients. Although type 2 diabetes mellitus (DM) is a major risk factor of AKI after MI, the underlying mechanism remains unclear. Here, we examined the roles of renal Toll-like receptors (TLRs) in the impact of DM on AKI after MI. MI was induced by coronary artery ligation in Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a rat DM model, and Long-Evans-Tokushima-Otsuka (LETO) rats, nondiabetic controls. Sham-operated rats served as no-MI controls. Renal mRNA levels of TLR2 and myeloid differentiation factor 88 (MyD88) were significantly higher in sham-operated OLETF rats than in sham-operated LETO rats, although levels of TLR1, TLR3, and TLR4 were similar. At 12 h after MI, protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the kidney were elevated by 5.3- and 4.0-fold, respectively, and their mRNA levels were increased in OLETF but not LETO rats. The increased KIM-1 and NGAL expression levels after MI in the OLETF kidney were associated with upregulated expression of TLR1, TLR2, TLR4, MyD88, IL-6, TNF-α, chemokine (C-C motif) ligand 2, and transforming growth factor-β1 and also with activation of p38 MAPK, JNK, and NF-κB. Cu-CPT22, a TLR1/TLR2 antagonist, administered before MI significantly suppressed MI-induced upregulation of KIM-1, TLR2, TLR4, MyD88, and chemokine (C-C motif) ligand 2 levels and activation of NF-κB, whereas NGAL levels and IL-6 and TNF-α expression levels were unchanged. The results suggest that DM increases the susceptibility to AKI after acute MI by augmented activation of renal TLRs and that TLR1/TLR2-mediated signaling mediates KIM-1 upregulation after MI.NEW & NOTEWORTHY This is the first report to demonstrate the involvement of Toll-like recpetors (TLRs) in diabetes-induced susceptibility to acute kidney injury after acute myocardial infarction. We propose that the TLR1/TLR2 heterodimer may be a new therapeutic target for the prevention of acute kidney injury in diabetic patients.

197 ELEVATION OF PLASMA FATTY ACID-BINDING PROTEIN 4 LEVEL CONTRIBUTES TO BLOOD PRESSURE ELEVATION AND INSULIN RESISTANCE IN ESSENTIAL HYPERTENSION

Objectives: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and the association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. Methods: We examined the association between insulin sensitivity (M value) determined by the hyperinsulinemic-euglycemic clamp and serum FABP4 concentration in 18 normotensives (NT) and 30 non-treated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) using a cut-off point of mean ± 1 SD of the M value in NT. Results: Serum FABP4 level was significantly higher in the EHT-R than in the NT (24.2 ± 2.0 vs. 15.3 ± 1.5 ng/ml), whereas elevation of FABP4 level in the EHT-S (20.7 ± 2.1 ng/ml) was not statistically significant. In all of the subjects, FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides level and negatively correlated with the M value. Multiple regression analysis showed that the M value, BMI, and blood pressure were independent determinants of FABP4 concentration. On the other hand, FABP4 level was an independent predictor of blood pressure after adjustment of age, gender, and BMI. Conclusions: Hyper-FABP4-emia is related to high blood pressure and insulin resistance in patients with essential hypertension. Circulating FABP4 may contribute to blood pressure elevation and atherogenic metabolic phenotype in hypertensive patients.

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study

Background/Aims: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. Methods: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. Results: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95%CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). Conclusion: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen.

Detection of Urinary Mulberry Bodies Leads to Diagnosis of Fabry Cardiomyopathy: A Simple Clue in the Urine Sediment

Fabry disease is an X-linked lysosomal storage disease characterized by globotriaosyceramide accumulation because of genetic loss/deficiency of α-galactosidase A (α-Gal A) activity. Clinical symptoms of classic Fabry disease, such as acroparethesia and neuropathic pain, typically become apparent in childhood and adolescence. Clinical manifestations in adulthood include cardiac and renal diseases, which are the main causes of death. Life expectancy of untreated Fabry males is ≈50 years. Myocardial involvement in Fabry disease is potentially misdiagnosed as hypertrophic cardiomyopathy unless careful workup of the patient, including pathological and genetic tests, is performed. The presence of chronic kidney disease with proteinuria in patients with ventricular hypertrophy leads to further analyses for diagnosis of Fabry disease. Although deterioration of renal function, leading to end-stage renal disease, is a typical manifestation of classical Fabry disease, a cardiac variant of Fabry disease, often accompanied by mild proteinuria, has also been reported. A 52-year-old man with ventricular hypertrophy and a history of acroparethesia during childhood was referred …

199 SERUM FABP4 (A-FABP/AP2) AND FABP5 (E-FABP/MAL1) AS POSSIBLE BIOMARKERS OF INSULIN RESISTANCE AND CORONARY ATHEROSCLEROSIS

Objectives: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) and 5 (FABP5/E-FABP/mal1) are expressed in both adipocytes and macrophages and paly important roles of development of insulin resistance and atherosclerosis. Recent studies have shown that elevated serum FABP4 is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the association of FABP5 concentration with insulin resistance and atherosclerosis. Methods: We determined serum levels of FABP4 and FABP5 and severity of coronary stenosis by the modified Gensinis score in coronary angiography in 34 male patients with stable angina pectoris. Results: Serum FABP5 concentration (1.2 ± 0.1 ng/ml) was about 15-fold lower than FABP4 level (18.1 ± 1.5 ng/ml). Both levels of FABP4 and FABP5 were positively correlated with age (r = 0.35, 0.42, respectively), body mass index (BMI; r = 0.42, 0.37), fasting plasma glucose (r = 0.43, 0.35), insulin (r = 0.50, 0.40) and HOMA-R (r = 0.55, 0.45) and negatively correlated with estimated glomerular filtration rate (eGFR; r = -0.34, -0.42). Multiple regression analysis showed that HOMA-R was an independent determinant of both FABP4 and FABP5 after adjustment of age, BMI, and eGFR. Coronary stenosis score was not correlated with age, blood pressure, HOMA-R or LDL cholesterol. There was a significant correlation of coronary stenosis score with FABP4 level (r = 0.37, p = 0.003) but not with FABP5 level (r = 0.26, p = 0.138). Conclusions: Concentration of FABP4 and FABP5 might be novel biomarkers of insulin resistance. FABP4 level might additionally predict severity of coronary atherosclerosis.