Oxidative stress and cellular stress response in diabetic nephropathy.
Oxidative stress has been suggested to play a main role in the pathogenesis of type 2 diabetes mellitus and its complications. As a consequence of this increased oxidative status, a cellular-adaptive response occurs requiring functional chaperones, antioxidant production, and protein degradation. This study was designed to evaluate systemic oxidative stress and cellular stress response in patients suffering from type 2 diabetes-induced nephropathy and in age-matched healthy subjects. Systemic oxidative stress has been evaluated by measuring advanced glycation end-products (pentosidine), protein oxidation (protein carbonyls [DNPH]), and lipid oxidation (4-hydroxy-2-nonenal [HNE] and F2-isoprostanes) in plasma, lymphocytes, and urine, whereas the lymphocyte levels of the heat shock proteins (Hsps) heme oxygenase-1 (HO-1), Hsp70, and Hsp60 as well as thioredoxin reductase-1 (TrxR-1) have been measured to evaluate the systemic cellular stress response. We found increased levels of pentosidine (P < 0.01), DNPH (P < 0.05 and P < 0.01), HNE (P < 0.05 and P < 0.01), and F2-isoprostanes (P < 0.01) in all the samples from type 2 diabetic patients with nephropathy with respect to control group. This was paralleled by a significant induction of cellular HO-1, Hsp60, Hsp70, and TrxR-1 (P < 0.05 and P < 0.01). A significant upregulation of both HO-1 and Hsp70 has been detected also in lymphocytes from type 2 diabetic patients without uraemia. Significant positive correlations between DNPH and Hsp60, as well as between the degree of renal failure and HO-1 or Hsp70, also have been found in diabetic uremic subjects. In conclusion, patients affected by type 2 diabetes complicated with nephropathy are under condition of systemic oxidative stress, and the induction of Hsp and TrxR-1 is a maintained response in counteracting the intracellular pro-oxidant status.
Calabrese
Vittorio
V
Department of Chemistry, Faculty of Medicine, University of Catania, 95100 Catania, Italy calabres@mbox.unict.it
Mancuso
Cesare
C
Sapienza
Maria
M
Puleo
Eduardo
E
Calafato
Stella
S
Cornelius
Carolin
C
Finocchiaro
Manuela
M
Mangiameli
Andrea
A
Di Mauro
Maurizio
M
Stella
Anna Maria Giuffrida
AM
Castellino
Pietro
P
D000447:Aldehydes / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D018834:Chaperonin 60 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D028441:F2-Isoprostanes / Q000097:blood / Q000652:urine; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D050050:Protein Carbonylation; D051437:Renal Insufficiency / Q000473:pathology; D054481:Thioredoxin Reductase 1 / Q000378:metabolism
D000447:Aldehydes; D018834:Chaperonin 60; D028441:F2-Isoprostanes; D018840:HSP70 Heat-Shock Proteins; D001120:Arginine; C062187:pentosidine; D051547:Heme Oxygenase-1; D054481:Thioredoxin Reductase 1; C027576:4-hydroxy-2-nonenal; D008239:Lysine