TY - JOUR
T1 - Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation
AU - Folli, Franco
AU - Guzzi, Valeria
AU - Perego, Lucia
AU - Coletta, Dawn K.
AU - Finzi, Giovanna
AU - Placidi, Claudia
AU - la Rosa, Stefano
AU - Capella, Carlo
AU - Socci, Carlo
AU - Lauro, Davide
AU - Tripathy, Devjit
AU - Jenkinson, Christopher
AU - Paroni, Rita
AU - Orsenigo, Elena
AU - Cighetti, Giuliana
AU - Gregorini, Luisa
AU - Staudacher, Carlo
AU - Secchi, Antonio
AU - Bachi, Angela
AU - Brownlee, Michael
AU - Fiorina, Paolo
PY - 2010
Y1 - 2010
N2 - Background: In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/ microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold. Methods and Findings: We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3- 3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant. Conclusions: Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.
AB - Background: In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/ microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold. Methods and Findings: We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3- 3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant. Conclusions: Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.
UR - http://www.scopus.com/inward/record.url?scp=78649454844&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649454844&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0009923
DO - 10.1371/journal.pone.0009923
M3 - Article
C2 - 20360867
AN - SCOPUS:78649454844
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 3
M1 - e9923
ER -