PMID- 20558542
OWN - NLM
STAT- MEDLINE
DCOM- 20100721
LR  - 20211020
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 21
IP  - 7
DP  - 2010 Jul
TI  - Immunoglobulin light chains activate tubular epithelial cells through redox 
      signaling.
PG  - 1165-73
LID - 10.1681/ASN.2009101089 [doi]
AB  - The renal proximal tubule metabolizes circulating low-molecular-weight proteins 
      such as Ig free light chains. In the setting of plasma cell dyscrasias, the 
      burden of filtered protein can be very high. Endocytosis of certain nephrotoxic 
      light chains induces H(2)O(2) production and monocyte chemoattractant protein-1 
      (MCP-1) release, leading to recruitment of inflammatory cells and interstitial 
      fibrosis, but how these processes are linked mechanistically is not well 
      understood. This study investigated the relationship between H(2)O(2) generated 
      after light chain endocytosis by human proximal tubular (HK-2) cells and 
      activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two 
      different light chains upregulated c-Src activity, which increased the production 
      of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. 
      Inhibition of c-Src activity and silencing c-Src expression abrogated the light 
      chain-induced MCP-1 response, but had no effect on H(2)O(2), indicating that 
      production of H(2)O(2) is upstream of c-Src in the signaling cascade. Silencing 
      megalin and cubilin expression inhibited the MCP-1 response, whereas 
      extracellular catalase did not, indicating that endocytosis is required and that 
      intracellular generation of reactive oxygen species activates c-Src. These data 
      show that intracellular H(2)O(2) induced by endocytosis of monoclonal free light 
      chains oxidizes and activates c-Src, which promotes release of MCP-1.
FAU - Basnayake, Kolitha
AU  - Basnayake K
AD  - University of Birmingham, Edgbaston, Birmingham, United Kingdom.
FAU - Ying, Wei-Zhong
AU  - Ying WZ
FAU - Wang, Pei-Xuan
AU  - Wang PX
FAU - Sanders, Paul W
AU  - Sanders PW
LA  - eng
GR  - P30 DK079337/DK/NIDDK NIH HHS/United States
GR  - R01 DK046199-17/DK/NIDDK NIH HHS/United States
GR  - R01 DK046199/DK/NIDDK NIH HHS/United States
GR  - I01 CX001326/CX/CSRD VA/United States
GR  - R01 DK46199/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100617
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Albumins)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immunoglobulin Light Chains)
RN  - 0 (Interleukin-6)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (intrinsic factor-cobalamin receptor)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (CSK Tyrosine-Protein Kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.10.23 (CSK protein, human)
SB  - IM
CIN - J Am Soc Nephrol. 2010 Jul;21(7):1065-6. PMID: 20558535
MH  - Albumins/metabolism
MH  - CSK Tyrosine-Protein Kinase
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Endocytosis/*physiology
MH  - Epithelial Cells/cytology/*physiology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Hydrogen Peroxide/metabolism
MH  - Immunoglobulin Light Chains/*physiology
MH  - Interleukin-6/metabolism
MH  - Kidney Tubules, Proximal/cytology/*physiology
MH  - Low Density Lipoprotein Receptor-Related Protein-2/genetics/metabolism
MH  - Oxidation-Reduction
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - src-Family Kinases
PMC - PMC3152234
EDAT- 2010/06/19 06:00
MHDA- 2010/07/22 06:00
PMCR- 2011/07/01
CRDT- 2010/06/19 06:00
PHST- 2010/06/19 06:00 [entrez]
PHST- 2010/06/19 06:00 [pubmed]
PHST- 2010/07/22 06:00 [medline]
PHST- 2011/07/01 00:00 [pmc-release]
AID - ASN.2009101089 [pii]
AID - 2009101089 [pii]
AID - 10.1681/ASN.2009101089 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2010 Jul;21(7):1165-73. doi: 10.1681/ASN.2009101089. Epub 2010 
      Jun 17.