キシ　セイジ   Seiji Kishi   岸　誠司    所属   川崎医科大学  医学部 臨床医学　腎臓・高血圧内科学    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy.
掲載誌名	正式名：PloS one 略　 称：PLoS One ISSNコード：19326203/19326203
掲載区分	国外
巻・号・頁	14(5),pp.e0216788
著者・共著者	Akiko Sakurai, Hiroyuki Ono, Arisa Ochi, Motokazu Matsuura, Sakiya Yoshimoto, Seiji Kishi, Taichi Murakami, Tatsuya Tominaga, Kojiro Nagai, Hideharu Abe, Toshio Doi
発行年月	2019
概要	Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R2 = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN.
DOI	10.1371/journal.pone.0216788
PMID	31150422