transforming-growth-factor-alpha and Hypertension

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Blood Pressure; Cells, Cultured; Dependovirus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; ErbB Receptors; Extracellular Matrix; Female; Gene Transfer Techniques; Genetic Vectors; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Mice, 129 Strain; Mice, Knockout; Middle Aged; Nephrectomy; Phosphorylation; Renin-Angiotensin System; Signal Transduction; Time Factors; Transforming Growth Factor alpha

Sphingosine-1-phosphate (S1P), a multifunctional phospholipid, regulates vascular cell function. Whether S1P influences vascular inflammatory responses, particularly in hypertension, is unclear. We tested the hypothesis that S1P is a proinflammatory mediator signaling through receptor tyrosine kinase transactivation and that responses are amplified in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSPs), a model in which we demonstrated Edg1 (S1P1 receptor) to be a candidate gene for salt-sensitive hypertension. Vascular smooth muscle cell from Wistar-Kyoto rats and SHRSPs were studied. S1P receptor subtypes, S1P1 and S1P2, were similarly expressed in Wistar-Kyoto rats and SHRSPs. S1P induced phosphorylation of epidermal growth factor receptor and platelet-derived growth factor and activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, with amplified effects in SHRSPs versus Wistar-Kyoto rats. Inhibition of epidermal growth factor receptor and platelet-derived growth factor (with AG1478 and AG1296, respectively) abolished S1P-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase in Wistar-Kyoto rats with variable effects in SHRSPs. Vascular smooth muscle cell inflammation was evaluated by expression of adhesion molecules and functional responses assessed by monocyte adhesion. S1P stimulated expression of intercellular adhesion molecule 1 and vascular cell adhesion protein 1 and promoted monocyte adhesion, particularly in SHRSP cells. S1P-mediated inflammation was blunted by AG1478 and AG1296 in SHRSP cells. VPC23019, a S1P1 receptor antagonist, inhibited S1P-induced mitogen-activated protein kinase phosphorylation, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression, and monocyte adhesion. Our data indicate that molecular processes underlying vascular inflammation and cell adhesion in SHRSPs involve S1P/S1P1 receptors and phosphorylation of receptor tyrosine kinases. We identify a novel pathway linking S1P/S1P1 receptors to specific proinflammatory signaling pathways through epidermal growth factor receptor and platelet-derived growth factor transactivation, a process that is upregulated in SHRSPs. Such molecular events may contribute to vascular inflammation in hypertension.

Topics: Analysis of Variance; Animals; Blotting, Western; Cell Adhesion; Cells, Cultured; Hypertension; Inflammation; Lysophospholipids; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Rats; Rats, Inbred WKY; Rats, Wistar; Receptors, Lysosphingolipid; Receptors, Platelet-Derived Growth Factor; Species Specificity; Sphingosine; Transforming Growth Factor alpha; Up-Regulation