The death ligand TRAIL in diabetic nephropathy.
Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death-related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-kappaB, and inhibition of NF-kappaB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN.
Lorz
Corina
C
Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
Benito-Martín
Alberto
A
Boucherot
Anissa
A
Ucero
Alvaro C
AC
Rastaldi
Maria Pia
MP
Henger
Anna
A
Armelloni
Silvia
S
Santamaría
Beatriz
B
Berthier
Celine C
CC
Kretzler
Matthias
M
Egido
Jesus
J
Ortiz
Alberto
A
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001706:Biopsy; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism*
D008024:Ligands; D016328:NF-kappa B; D053244:Osteoprotegerin; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D005947:Glucose