CXCL16 is expressed in podocytes and acts as a scavenger receptor for oxidized low-density lipoprotein.
Podocytes are a crucial cell type in the kidney and play an important role in the pathology of glomerular kidney diseases like membranous nephropathy (MN). The identification of new factors involved in the progression of glomerular kidney diseases is of great importance to the development of new strategies for the treatment of renal injury. Here we demonstrate that CXCL16 and ADAM10 are constitutively expressed in human podocytes in normal renal tissue. Proinflammatory cytokines like interferon-gamma and tumor necrosis factor-alpha induced the expression of cellular CXCL16 and the release of its soluble form from human podocytes. Using different metalloproteinase inhibitors, we provide evidence that ADAM10 is involved in the interferon-gamma- and tumor necrosis factor-alpha-induced shedding of CXCL16 from human podocytes. In addition, ADAM10 knockdown by siRNA significantly increased both CXCL16 levels and, surprisingly, its ADAM17-mediated release. Notably, targeting of CXCL16 in human podocytes both decreased the chemotaxis of CXCR6-expressing T cells and strongly reduced oxidized low-density lipoprotein uptake in human podocytes. Importantly, in kidney biopsies of patients with MN, increased glomerular CXCL16 expression was accompanied by high levels of oxidized low-density lipoprotein and decreased expression of ADAM10. In addition, we found increased glomerular ADAM17 expression in patients diagnosed with MN. In summary, we presume important roles for CXCL16, ADAM10, and ADAM17 in the development of MN, suggesting these proteins as new therapeutic targets in this glomerular kidney disease.
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. p.gutwein@med.uni-frankfurt.de
Paul
P
Gutwein
Mohamed Sadek
MS
Abdel-Bakky
Anja
A
Schramme
Kai
K
Doberstein
Nicole
N
Kämpfer-Kolb
Kerstin
K
Amann
Ingeborg A
IA
Hauser
Nicholas
N
Obermüller
Christine
C
Bartel
Abdel-Aziz H
AA
Abdel-Aziz
El Sayed M
el SM
El Sayed
Josef
J
Pfeilschifter
D051722:ADAM Proteins / Q000276:immunology / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D005260:Female; D005455:Fluorescent Antibody Technique; D015433:Glomerulonephritis, Membranous / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D050199:Podocytes / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D051116:Receptors, Scavenger / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human