ArticleNature medicine2009
Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy.
Article in Nature medicine, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 243 papers.
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Who cites it
243 citing papers in PubMed, 420 citations in OpenAlex.
- Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2013Trial
- Metabolic reprogramming in diabetic panvascular disease: Molecular mechanism and therapeutic strategies.iScience · 2026Review
- Bibliometric analysis and visualization of inflammation in the field of diabetic retinopathy research (2006-2025).Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2026Article
- The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications.Journal of biomedical science · 2026Review
- Dysfunction of the Neurovascular Unit in Diabetic Retinopathy: Advances from Molecular Mechanisms to Targeted Interventions.Stem cell reviews and reports · 2026Review
- Kinase regulation of miRNA networks in cardiometabolic disease: emerging pathways to precision therapy.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Advances in the differentiation of induced pluripotent stem cells into vascular cells for the treatment of diabetic microvascular disease.Cardiovascular diabetology · 2026Review
- Molecular stress and neurovascular injury in the diabetic retina.The Journal of clinical investigation · 2026Review
- Non-invasive characterization of pericyte dysfunction in mouse brain using functional ultrasound localization microscopy.Nature biomedical engineering · 2026Article
- Role of Antioxidants in Diseases and its Impact on Mitochondria with A Focus on Diabetes: An Overview.Current drug research reviews · 2026Review
- Clinical histopathology and pathogenesis of macular telangiectasia type 2.Progress in retinal and eye research · 2026Review
- Spatially convergent functional MRI signatures of diabetes and male sex identify genetic vulnerabilities to accelerated brain ageing.Brain communications · 2026Article
- Cold atmospheric plasma is a promising strategy for treating diabetic retinopathy.Journal of translational medicine · 2025Review
- Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy.Nature communications · 2025Article
- Pathophysiological Mechanisms of Diabetes-Induced Macrovascular and Microvascular Complications: The Role of Oxidative Stress.Medical sciences (Basel, Switzerland) · 2025Review
- Review
- Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications.International journal of molecular sciences · 2025Review
- Functionally distinct pericyte subsets differently regulate amyloid-β deposition in patients with Alzheimer's disease.Brain pathology (Zurich, Switzerland) · 2025Article
- Oxidative stress in diabetes mellitus and its complications: From pathophysiology to therapeutic strategies.Chinese medical journal · 2025Review
- Senescent endothelial cells: a potential target for diabetic retinopathy.Angiogenesis · 2024Review
183 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.