CXCL16 and oxLDL are induced in the onset of diabetic nephropathy.
Diabetic nephropathy (DN) is a major cause of end-stage renal failure worldwide. Oxidative stress has been reported to be a major culprit of the disease and increased oxidized low density lipoprotein (oxLDL) immune complexes were found in patients with DN. In this study we present evidence, that CXCL16 is the main receptor in human podocytes mediating the uptake of oxLDL. In contrast, in primary tubular cells CD36 was mainly involved in the uptake of oxLDL. We further demonstrate that oxLDL down-regulated alpha(3)-integrin expression and increased the production of fibronectin in human podocytes. In addition, oxLDL uptake induced the production of reactive oxygen species (ROS) in human podocytes. Inhibition of oxLDL uptake by CXCL16 blocking antibodies abrogated the fibronectin and ROS production and restored alpha(3) integrin expression in human podocytes. Furthermore we present evidence that hyperglycaemic conditions increased CXCL16 and reduced ADAM10 expression in podocytes. Importantly, in streptozotocin-induced diabetic mice an early induction of CXCL16 was accompanied by higher levels of oxLDL. Finally immunofluorescence analysis in biopsies of patients with DN revealed increased glomerular CXCL16 expression, which was paralleled by high levels of oxLDL. In summary, regulation of CXCL16, ADAM10 and oxLDL expression may be an early event in the onset of DN and therefore all three proteins may represent potential new targets for diagnosis and therapeutic intervention in DN.
Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt, Frankfurt, Germany. p.gutwein@med.uni-frankfurt.de
Paul
P
Gutwein
Mohamed Sadek
MS
Abdel-Bakky
Kai
K
Doberstein
Anja
A
Schramme
Janet
J
Beckmann
Liliana
L
Schaefer
Kerstin
K
Amann
Anke
A
Doller
Nicole
N
Kämpfer-Kolb
Abdel-Aziz H
AA
Abdel-Aziz
El Sayed M
el SM
El Sayed
Josef
J
Pfeilschifter
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D039422:Integrin alpha3 / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D051116:Receptors, Scavenger / Q000378:metabolism*; D016896:Treatment Outcome
D018955:CD36 Antigens; C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D039422:Integrin alpha3; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse