Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is frequently associated with the development of renal vascular and glomerular fibrosis. The purpose of the present study was to investigate whether epidermal growth factor receptor (EGFR) activation participates in the development of renal fibrosis and to test if blockade of EGFR activation would have therapeutic effects. Experiments were performed during nitric oxide (NO) deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME treatment, animals developed hypertension associated to deterioration of renal structure and function. Over the same period, EGFR was activated twofold within glomeruli. This activation was accompanied by increased activity of the mitogen-activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly with L-NAME, normalized MAPK activation and collagen I expression and prevented the decline of renal function and the development of fibrosis. Since endothelin mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was tested in transgenic mice expressing luciferase under the control of collagen I-alpha2 promoter: In renal cortex of these animals, the endothelin-induced collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor. These results provide the first evidence that EGFR activation plays an important role in the progression of renal vascular and glomerular fibrosis.
 ...
PMID:Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition. 1503 24

In chronic kidney disease, activation of the epidermal growth factor receptor (EGFR) leads to cardiac hypertrophy, which affects morbidity and mortality. In patients with renal insufficiency and heart failure, the expression of midkine, a heparin-binding growth factor, is increased. Therefore, we investigated the association between midkine and EGFR in the induction of cardiac hypertrophy and dysfunction in chronic kidney disease. We performed subtotal nephrectomies in midkine-knockout mice and wild-type mice. We found that subtotal nephrectomy-induced cardiac hypertrophy and phosphorylation of extracellular signal-regulated kinase 1/2 and AKT were attenuated in midkine-knockout mice compared with wild-type mice. An antiphosphotyrosine receptor antibody array was used to demonstrate that EGFR phosphorylation in the heart was also lower in midkine-knockout mice than in wild-type mice. Midkine induced EGFR, extracellular signal-regulated kinase 1/2, and AKT phosphorylation and led to hypertrophy in neonatal rat cardiomyocytes. Pretreatment with EGFR inhibitors or EGFR silencing suppressed midkine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and AKT, induction of fetal cardiac gene expression, and hypertrophy in cardiomyocytes. To confirm the association between midkine and EGFR in vivo, mice subjected to subtotal nephrectomy were treated with the EGFR inhibitor gefitinib. Gefitinib treatment attenuated subtotal nephrectomy-induced cardiac hypertrophy. These results indicate that midkine might be a key mediator of cardiorenal interactions through EGFR activation, which plays a crucial role in cardiac hypertrophy in chronic kidney disease.
Hypertension 2016 May
PMID:Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease. 2697 3