Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy.
Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is crucial for the initiation of diabetic pathologies. In the retina, pericyte apoptosis and the formation of acellular capillaries, the most specific vascular pathologies attributed to hyperglycemia, is linked to the loss of platelet-derived growth factor (PDGF)-mediated survival actions owing to unknown mechanisms. Here we show that hyperglycemia persistently activates protein kinase C-delta (PKC-delta, encoded by Prkcd) and p38alpha mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-delta signaling, Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor-beta dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis independently of nuclear factor-kappaB (NF-kappaB) signaling. We observed increased PKC-delta activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wild-type mice, diabetic Prkcd(-/-) mice did not show activation of p38alpha MAPK or SHP-1, inhibition of PDGF signaling in vascular cells or the presence of acellular capillaries. We also observed PKC-delta, p38alpha MAPK and SHP-1 activation in brain pericytes and in the renal cortex of diabetic mice. These findings elucidate a new signaling pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications.
Geraldes
Pedro
P
Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Boston, Massachusetts, USA.
Hiraoka-Yamamoto
Junko
J
Matsumoto
Motonobu
M
Clermont
Allen
A
Leitges
Michael
M
Marette
Andre
A
Aiello
Lloyd P
LP
Kern
Timothy S
TS
King
George L
GL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C497259:Prkcd protein, mouse; D020797:Receptor, Platelet-Derived Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; C509962:Mak protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D005947:Glucose