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- Title
Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells.
- Authors
Gava, Elisandra; Samad-Zadeh, Arman; Zimpelmann, Joseph; Bahramifarid, Nasim; Kitten, Gregory T.; Santos, Robson A.; Touyz, Rhian M.; Burns, Kevin D.
- Abstract
Background. In the diabetic kidney, stimulation of mitogen-activated protein kinases (MAPKs) leads to extracellular matrix protein synthesis. In the proximal tubule, angiotensin-(1–7) [Ang-(1–7)] blocks activation of MAPKs by angiotensin II. We studied the effect of Ang-(1–7) on signalling responses in LLC-PK1 cells in normal (5 mM) or high (25 mM) glucose. Methods. The p38 MAPK was assayed by immunoblot, Src homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity was measured after immunoprecipitation, cell protein synthesis was determined by [3H]-leucine incorporation and transforming growth factor-β1 (TGF-β1), fibronectin and collagen IV were assayed by immunoblots and/or ELISA. Results. High glucose stimulated p38 MAPK. This response was inhibited by Ang-(1–7) in a concentration-dependent fashion, an effect reversed by the receptor Mas antagonist A-779. Ang-(1–7) increased SHP-1 activity, via the receptor Mas. An inhibitor of tyrosine phosphatase, phenylarsine oxide, reversed the inhibitory effect of Ang-(1–7) on high glucose-stimulated p38 MAPK. Ang-(1–7) inhibited high glucose-stimulated protein synthesis, and blocked the stimulatory effect of glucose on TGF-β1. Conversely, Ang-(1–7) had no effect on glucose-stimulated synthesis of fibronectin or collagen IV. Conclusions. These data indicate that in proximal tubular cells, binding of Ang-(1–7) to the receptor Mas stimulates SHP-1, associated with the inhibition of glucose-stimulated p38 MAPK. Ang-(1–7) selectively inhibits glucose-stimulated protein synthesis and TGF-β1. In diabetic nephropathy, Ang-(1–7) may partly counteract the profibrotic effects of high glucose.
- Subjects
ANGIOTENSINS; ENZYME activation; PROTEIN-tyrosine phosphatase; GLUCOSE; CELLULAR signal transduction; CELL physiology; MITOGEN-activated protein kinases; PROTEIN synthesis; DIABETIC nephropathies
- Publication
Nephrology Dialysis Transplantation, 2009, Vol 24, Issue 6, p1766
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfn736