Related Experiment Video

Updated: May 10, 2026

Antagonistic Effect of Jiawei Shengjiang San on a Rat Model of Diabetic Nephropathy: Related to EGFR/MAPK3/1 Signaling Pathway
08:15

Antagonistic Effect of Jiawei Shengjiang San on a Rat Model of Diabetic Nephropathy: Related to EGFR/MAPK3/1 Signaling Pathway

Published on: May 10, 2024

Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular

Saghir Akhtar1, Mariam H M Yousif, Gursev S Dhaunsi

  • 1Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait.

Plos One
|July 5, 2013
PubMed

Insights

Diabetes causes vascular problems by affecting ErbB2 signaling. Inhibiting ErbB2 improves blood vessel function in diabetic rats, suggesting new treatment strategies for diabetic vascular complications.

Area of Science:

  • Biomedical Science
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Diabetes mellitus is a major cause of vascular complications, yet the precise signaling pathways involved remain unclear.
  • Receptor tyrosine kinases, such as ErbB2 (HER2/Neu), play critical roles in cellular signaling and have been implicated in various disease states.

Purpose of the Study:

  • To investigate the role of ErbB2 in mediating diabetes-induced vascular dysfunction.
  • To explore the signaling mechanisms downstream of ErbB2 activation in the context of diabetes.

Main Methods:

  • Utilized a streptozotocin-induced type 1 diabetes rat model.
  • Administered AG825, a specific ErbB2 inhibitor, both chronically and acutely (ex vivo).
  • Assessed vascular reactivity of the perfused mesenteric vascular bed (MVB) to norepinephrine and carbachol.
  • Analyzed ErbB2 phosphorylation, Rho kinases (ROCKs), and ERK1/2 activation in MVB and cultured vascular smooth muscle cells (VSMC).
  • Investigated ErbB2-EGFR heterodimerization and downstream signaling blockade using AG1478 and anti-ErbB2 siRNA.

Main Results:

  • Diabetes induced hyper-reactivity to norepinephrine and attenuated responsiveness to carbachol in the MVB.
  • Chronic AG825 treatment significantly corrected these diabetes-induced vascular dysfunctions.
  • Diabetes enhanced ErbB2 phosphorylation at key tyrosine residues (Y1221/1222, Y1248, Y877) in the MVB.
  • ErbB2 phosphorylation correlated with activation of ROCKs and ERK1/2 in diabetic MVB and VSMC.
  • Inhibition of ErbB2 (AG825) or EGFR (AG1478), or knockdown of ErbB2, attenuated these signaling pathways.
  • Evidence suggested ErbB2 heterodimerization with EGFR, sharing common downstream effectors.

Conclusions:

  • ErbB2 is a critical upstream mediator of diabetes-induced vascular dysfunction.
  • ErbB2 signaling activates ROCKs and ERK1/2 pathways, contributing to vascular complications in diabetes.
  • Targeting the ErbB2 pathway presents a potential therapeutic strategy for managing diabetes-related vascular issues.

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...