Biomedical subjects

Kei Fukami

Publications and source records attributed to Kei Fukami.

4 recordsLinked to original sources

PubMed2005

Polymorphonuclear leukocytes may impair endothelial function: results of crossover randomized study of lipid-lowering therapies.

OBJECTIVES: To examine whether polymorphonuclear leukocytes (PMNs) in hypercholesterolemia (HC) are activated to generate large amount of superoxide in vivo and hence impair endothelial function and, if so, whether statins, which possess anti-inflammatory properties, may restore PMN-mediated endothelial dysfunction. METHODS AND RESULTS: At baseline, subjects with HC showed impaired endothelial function (P<0.001), estimated by flow-mediated vasodilation of the brachial artery, and increased susceptibility of low-density lipoprotein (LDL) to oxidation (P<0.0001) compared with control subjects. PMNs obtained from HC produced greater amount of superoxide (P<0.0001), showed higher adhesiveness to cultured endothelial cells (HUVECs) (P<0.0001), and impaired endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation of HUVECs compared with controls (P<0.001). Crossover administration of fluvastatin or colestimide for 3 months lowered LDL to the same levels (P<0.001 for both). Endothelial function was restored (P<0.0001). LDL oxidation (P<0.0001) and superoxide release from PMNs (P<0.0001) were diminished only in fluvastatin but not in colestimide arm. Fluvastatin attenuated PMN adhesion to HUVECs (P<0.0001) and restored eNOS Ser1177 phosphorylation of HUVECs (P<0.001). CONCLUSIONS: Statins may improve endothelial function at least in part by inactivating neutrophils independently of LDL reduction. Our results raise a novel concept that polymorphonuclear leukocytes may attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis.

Anticholesteremic Agents↗

PubMed2005

Comparison of histological findings and parathyroid scintigraphy in hemodialysis patients with secondary hyperparathyroid glands.

To determine the usefulness of parathyroid scintigraphy in histological estimation for secondary hyperparathyroidism (2HPT) using Tc-99m sestamibi or Tc-99m tetrofosmin. Tc-99m sestamibi (MIBI) and Tc-99m tetrofosmin (Tetro) parathyroid imaging following double-phase study, magnetic resonance imaging (MRI), and ultrasound were performed on 14 patients with 2HPT. All patients underwent parathyroidectomy. The uptake of two tracers in parathyroid areas was compared with the histopathologic findings. Forty-nine parathyroid glands were surgically explored and histologically proven to be hyperplastic. Of these, 42 were diagnosed with nodular type (N-type) hyperplasia, and 7 with diffuse type (D-type) hyperplasia. MIBI and Tetro parathyroid imagings detected 34 and 35 parathyroid glands, respectively. The sensitivity of MIBI was determined to be 76.2% (32/42) for N-type, and 28.6% (2/7) for D-type. The sensitivity of Tetro was determined to be 78.6% (33/42) for N-type and 28.6% (2/7) for D-type. The sensitivity of both MIBI and Tetro was significantly higher for N-type than for D-type, 76.2% (32/42) vs. 28.6% (2/7) in MIBI, P = 0.022; 78.6% (33/42) vs. 28.6% (2/7) in Tetro, P = 0.015. The sensitivity of MRI was determined to be 76.2% (32/42) for N-type and 42.9% (3/7) for D-type, and the sensitivity of ultrasound was 71.4% (30/42) for N-type and 71.4% (5/7) for D-type. There was no significant difference in the sensitivity of MRI or ultrasound between N-type and D-type. The uptake ratios of MIBI and Tetro were also greater for N-type than for D-type. The detectability of both MIBI and Tetro was greater for N-type than for D-type. Tc-99m MIBI or Tc-99m Tetro parathyroid scintigraphy therefore may be used clinically to distinguish N-type from D-type parathyroid gland hyperplasia.

Adult↗

PubMed2005

Agents in development for the treatment of diabetic nephropathy.

Diabetic nephropathy is a leading cause of end-stage renal disease, and accounts for significant morbidity and mortality in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and haemodynamic factors, which activate common pathways that lead to renal damage. In the past, the treatment of diabetic nephropathy has focused on the control of hyperglycaemia. Newer targets, some of which are linked to glucose-dependent pathways, appear to be a major focus of new treatments directed against the development and progression of renal damage as a result of diabetes. It is anticipated that additional therapeutic approaches that inhibit both metabolic and haemodynamic pathways will include strategies that target growth factors, cytokines and intracellular second messengers. Such an approach is expected to lead to improved therapies for the treatment of diabetic nephropathy.

Clinical Trials as Topic↗

PubMed2004

AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin II type I receptor interaction.

BACKGROUND: The renin-angiotensin system (RAS) and the accumulation of advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy. Whether there is a functional interaction between the RAS and AGEs in diabetic nephropathy is not known. In this study, we investigated whether AGEs could activate autocrine angiotensin II (Ang II) signaling and subsequently induce transforming growth factor-beta (TGF-beta)-Smad signaling in cultured rat mesangial cells. METHODS: The intracellular formation of reactive oxygen species (ROS) was detected using the fluorescent probe CM-H2DCFDA. Ang II was measured by radioimmunoassay. TGF-beta released into media was quantitatively analyzed in an enzyme-linked immunosorbent assay (ELISA). Smad2, p27(Kip1) (p27), fibronectin, and receptor for AGEs (RAGE) protein expression were determined by Western blot analysis. TGF-beta-inducible promoter activity was analyzed by a luciferase assay. DNA synthesis was evaluated by 5-bomo-2'-deoxyuridine (BrdU) incorporation and de novo protein synthesis was determined by [3H]leucine incorporation. RESULTS: AGEs increased intracellular ROS generation in mesangial cells, and this effect was significantly inhibited by an antiserum against RAGE. AGEs also were found to stimulate Ang II production in a time- and dose-dependent manner, which was completely prevented by an antioxidant, N-acetylcysteine (NAC). AGE-induced TGF-beta overproduction was completely blocked by candesartan, an Ang II type 1 receptor (AT1R) antagonist. Both candesartan and neutralizing antibody against TGF-beta completely prevented AGEs-induced Smad2 phosphorylation and TGF-beta-inducible promoter activity. Furthermore, AGEs were found to inhibit DNA synthesis and to stimulate de novo protein synthesis and fibronectin production in association with up-regulation of p27. All of these phenomena were completely prevented by candesartan or a polyclonal antibody against TGF-beta. CONCLUSION: The present study suggests that AGE-RAGE-mediated ROS generation activates TGF-beta-Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II. This pathway may provide an important link between metabolic and haemodynamic factors in promoting the development and progression of diabetic nephropathy.

Angiotensin II↗