title: Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy.
abstract: Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF-α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ-diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-α and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Yamashita
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujimiya
authors.forename: Kanna
authors.initials: K
authors.lastname: Nagaishi
authors.forename: Koji
authors.initials: K
authors.lastname: Ataka
authors.forename: Marenao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Tsuchihashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002459:Cell Fusion; D002478:Cells, Cultured; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology* / Q000503:physiopathology*; D059305:Diet, High-Fat; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011384:Proinsulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D011384:Proinsulin