Faculty Opinions recommendation of Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop.

To investigate the novel interaction between endothelin-1 (ET-1) and cellular protein tyrosine kinases (PTK), we asked whether Ca2+ influx links ET-1 receptors to PTK activation. In glomerular mesangial cells, ET-1 stimulated a biphasic increase in PTK activity in anti-phosphotyrosine immunoprecipitates that temporally correlated with increased tyrosine phosphorylation of cellular proteins. ET-1 increased tyrosine phosphorylation of proteins in the cytosol and in a puncture distribution consistent with focal adhesions. Addition of ionomycin to increase Ca2+ influx stimulated PTK activity, and inhibition of extracellular Ca2+ influx blocked PTK activation by ET-1. ET-1 increased autophosphorylation of pp60c-src, which was mimicked by addition of ionomycin and inhibited by chelation of extracellular Ca2+. In addition, a selective PTK inhibitor blocked induction of c-fos mRNA by ionomycin, suggesting that Ca(2+)-stimulated PTKs contribute to a signaling pathway regulating immediate early gene expression. Taken together, these results demonstrate that ET-1 stimulates nonreceptor PTK activity, including pp60c-src, by activating Ca2+ channels and subsequent influx of extracellular Ca2+.

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Expression and Localization of Renal Endothelin-1, Endotehlin Receptors and Endothelin Converting Enzyme in Human Renal Biopsy with Rejection after Kidney Transplantation

Microscopy and Microanalysis ◽

10.1017/s1431927600035546 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 610-611

Author(s):

M. Kinjo ◽

J. Papadimitriou ◽

C. Drachenberg ◽

M. R. Weir ◽

C. Wei

Keyword(s):

Kidney Transplantation ◽

Mesangial Cells ◽

Collecting Duct ◽

Enzyme Level ◽

Tissue Level ◽

Renal Tissue ◽

Endothelin Receptors ◽

Converting Enzyme ◽

Endothelin 1 ◽

Endothelin Converting Enzyme

Endothelin (ET-1) is a potent renal and systemic vasoconstrictor and sodium regulating peptide. Endothelin synthesis in the kidney have been reported in glomerulus endothelial, epithelial and mesangial cells as well as in inner medullary collecting duct. Factors stimulating the production of endothelin include shear stress, hypoxia, vasoactive agents and cytokines. Endothelin binding to ET-A receptor in vascular smooth muscle cells stimulates vasoconstriction.Renal graft rejection is a major problem after kidney transplantation with severe renal damage and renal vasoconstriction. We hypothesized that renal tissue level of endothelin-1, endothelin receptors and endothelin converting enzyme (ECE) may increase in renal tissue with rejection after kidney transplantation. Therefore, the current study was designed to determine the endothelin-1 and endothelin receptors (ET-A and ET-B) as well as endothelin converting enzyme level by immunohistochemical staining (IHCS) in human renal tissue with rejection after kidney transplantation.

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