Role of Elf3 in diabetic nephropathy
櫻井, 明子 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
小野, 広幸 Tokushima University
Ochi, Arisa Tokushima University
松浦, 元一 Tokushima University KAKEN研究者をさがす
吉本, 咲耶 Tokushima University
岸, 誠司 Tokushima University KAKEN研究者をさがす
村上, 太一 Tokushima University KAKEN研究者をさがす
冨永, 辰也 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
長井, 幸二郎 Tokushima University KAKEN研究者をさがす
安部, 秀斉 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
土井, 俊夫 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
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.
© 2019 Sakurai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License( https://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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