Influence of native and hypochlorite-modified low-density lipoprotein on gene expression in human proximal tubular epithelium.
Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl(-)) an oxidant formed by the myeloperoxidase-H(2)O(2)-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1beta, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H(2)O(2)-halide system and HOCl-LDL in renal disease.
Porubsky
Stefan
S
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Schmid
Holger
H
Bonrouhi
Mahnaz
M
Kretzler
Matthias
M
Malle
Ernst
E
Nelson
Peter J
PJ
Gröne
Hermann-Josef
HJ
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001706:Biopsy; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007674:Kidney Diseases / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019459:Urothelium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D017931:DNA Primers; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D006997:Hypochlorous Acid; D000469:Alkaline Phosphatase