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  • Title: Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells.
    Author: Gava E, Samad-Zadeh A, Zimpelmann J, Bahramifarid N, Kitten GT, Santos RA, Touyz RM, Burns KD.
    Journal: Nephrol Dial Transplant; 2009 Jun; 24(6):1766-73. PubMed ID: 19144997.
    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-PK(1) 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 [(3)H]-leucine incorporation and transforming growth factor-beta1 (TGF-beta1), 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-beta1. 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-beta1. In diabetic nephropathy, Ang-(1-7) may partly counteract the profibrotic effects of high glucose.
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