Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

Background Inhibition of glucose influx into proximal tubular cells (PTCs) by sodium–glucose cotransporter 2 inhibitors revealed prominent therapeutic effects on diabetic kidney disease. Collectrin (CLTRN) serves as a chaperone for the trafficking of neutral amino acid (AA) transporters in the apical membranes of PTCs. We investigated the beneficial effects of reduced influx of AAs into PTCs in diabetes and obesity model of Cltrn−/y mice. Methods Cltrn+/y and Cltrn−/y mice at age 5 weeks were assigned to standard diet and streptozotocin and high-fat diet (STZ-HFD)–treated groups. Results At age 22–23 weeks, body weight and HbA1c levels significantly increased in STZ-HFD-Cltrn+/y compared with standard diet-Cltrn+/y; however, they were not altered in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. At age 20 weeks, urinary albumin creatinine ratio was significantly reduced in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. Under the treatments with STZ and HFD, the Cltrn gene deficiency caused significant increase in urinary concentration of AAs such as Gln, His, Gly, Thr, Tyr, Val, Trp, Phe, Ile, Leu, and Pro. In PTCs in STZ-HFD-Cltrn+/y, the enlarged lysosomes with diameter of 10 μm or more were associated with reduced autolysosomes, and the formation of giant lysosomes was prominently suppressed in STZ-HFD-Cltrn−/y. Phospho-mTOR and inactive form of phospho-transcription factor EB were reduced in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. Conclusions The reduction of AAs influx into PTCs inactivated mTOR, activated transcription factor EB, improved lysosome function, and ameliorated vacuolar formation of PTCs in STZ-HFD-Cltrn−/y mice

A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes

Background: Although animal models of PCOS have been used in many studies, none of them can reproduce both the reproductive and metabolic phenotypes of PCOS. In addition, behavioral parameters have not been evaluated in PCOS animal models. Purpose: We tried to produce an improved rat model of PCOS, and the reproductive, metabolic, and behavioral phenotypes of the model rats were evaluated. Methods: Female rats were implanted with silicon tubes containing oil-dissolved dihydrotestosterone (Oil-DHT) as a new PCOS model. Their phenotypes were compared with those of conventional PCOS model rats (DHT), into which tubes containing crystalline DHT were implanted, and non-DHT-treated rats (control). Results: Both the Oil-DHT and DHT rats showed greater body weight gain, food intake, and fat depot weight than the control rats. Furthermore, these groups showed fewer estrous stages and increased numbers of cystic follicles. The DHT rats exhibited lower ovarian and uterine weights than the control rats, whereas no such changes were observed in the Oil-DHT rats. The Oil-DHT and DHT rats showed less locomotor activity in the light phase than the control rats. Conclusions: Our proposed PCOS model reproduced both the reproductive and metabolic phenotypes of PCOS and may have potential for PCOS research

第二次世界大戦後の西ドイツ賠償問題とヨーロッパ地域秩序形成

本論文は、平成23-26年度科学研究費補助金基盤研究（A）（課題番号23243026）「日米特殊関係による東アジア地域再編の政治経済史研究」の助成を受けた研究成果の一部である