title: Erythrophagocytosis of lead-exposed erythrocytes by renal tubular cells: possible role in lead-induced nephrotoxicity.
abstract: BACKGROUND
  Nephrotoxicity associated with lead poisoning has been frequently reported in epidemiological studies, but the underlying mechanisms have not been fully described.
  
  
  OBJECTIVE
  We examined the role of erythrocytes, one of the major lead reservoirs, in lead-associated nephrotoxicity.
  
  
  RESULTS
  Co-incubation of lead-exposed human erythrocytes with HK-2 human renal proximal tubular cells resulted in renal tubular cytotoxicity, suggesting a role of erythrocytes in lead-induced nephrotoxicity. Morphological and flow cytometric analyses revealed that HK-2 cells actively phagocytized lead-exposed erythrocytes, which was associated with phosphatidylserine (PS) externalization on the erythrocyte membrane and generation of PS-bearing microvesicles. Increased oxidative stress and up-regulation of nephrotoxic biomarkers, such as NGAL, were observed in HK-2 cells undergoing erythrophagocytosis. Moreover, TGF-β, a marker of fibrosis, was also significantly up-regulated. We examined the significance of erythrophagocytosis in lead-induced nephrotoxicity in rats exposed to lead via drinking water for 12 weeks. We observed iron deposition and generation of oxidative stress in renal tissues of lead-exposed rats, as well as the histopathological alterations such as tubulointerstitial lesions, fibrosis, and up-regulation of KIM-1, NGAL, and TGF-β.
  
  
  CONCLUSIONS
  Our data strongly suggest that erythrophagocytosis and subsequent iron deposition in renal tubular cells could significantly enhance nephrotoxicity following lead exposure, providing insight on lead-associated kidney damages.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Kwon
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Noh
authors.forename: Keunyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Seojin
authors.initials: S
authors.lastname: Kang
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000818:Animals; D015415:Biomarkers; D004910:Erythrocyte Membrane; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress; D010587:Phagocytosis / Q000187:drug effects*; D010718:Phosphatidylserines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D015386:Hazardous Substances; D010718:Phosphatidylserines; D007854:Lead; D007501:Iron