Development of the treatment of diabetic nephropathy by targeting the TGF-β signaling

科学研究費補助金研究成果報告書研究種目: 基盤研究(B)研究期間: 2000～2002課題番号: 12470227研究代表者: 吉川 隆一（滋賀医科大学・学長）研究分担者: 羽田 勝計（滋賀医科大学・医学部・講師）研究分担者: 古家 大祐（滋賀医科大学・医学部・助手）研究分担者: 前川 聡（滋賀医科大学・医学部・助手

Nationwide multicentre kidney biopsy study of Japanese patients with type 2 diabetes

金沢大学医薬保健研究域医学系Background. The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-termobservations are limited. Methods. Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results. During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions. This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. © The Author 2017.Embargo Period 12 month

GW501516, a PPARδ Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFκB Pathway in Mice

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(−). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases

Seismic exploration at Fuji volcano with active sources : The outline of the experiment and the arrival time data

Fuji volcano (altitude 3,776m) is the largest basaltic stratovolcano in Japan. In late August and early September 2003, seismic exploration was conducted around Fuji volcano by the detonation of 500 kg charges of dynamite to investigate the seismic structure of that area. Seismographs with an eigenfrequency of 2 Hz were used for observation, positioned along a WSW-ENE line passing through the summit of the mountain. A total of 469 seismic stations were installed at intervals of 250-500 m. The data were stored in memory on-site using data loggers. The sampling interval was 4 ms. Charges were detonated at 5 points, one at each end of the observation line and 3 along its length. The first arrival times and the later-phase arrival times at each station for each detonation were recorded as data. P-wave velocities in the surface layer were estimated from the travel time curves near the explosion points, with results of 2.5 km/s obtained for the vicinity of Fuji volcano and 4.0 km5/s elsewhere

A Technique for Detecting Vortexes Using the Gradient of Doppler Velocity Data

We applied the method of detecting gust fronts and shear lines to the detection of the vortex in order to develop a simple technique for automatically detecting vortexes with Doppler velocity data obtained from a single Doppler radar. We calculated the velocity gradient along the range directions and along the azimuthal directions. If we recognize the shear pattern from the Doppler velocity field, a vortex (its location of the center and horizontal extent) will be detected. The analyses are performed on the Doppler velocity data of the cyclonic and the anticyclonic vortex close to Chitose Airport, Hokkaido, Japan on 22 September 1988. Rotational orientation and size are calculated by the conventional method for the analyses of a vortex and compared with the analyses by the vortex detection method. The diameter of the cyclonic vortex near 2,500 m in height remained about 10 km. Since we applied the method of detecting gust fronts and shear lines to this technique, the vortex and gust front (shear line) are detected at the same time. 1