Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells

Nephrol Dial Transplant. 2009 Jun;24(6):1766-73. doi: 10.1093/ndt/gfn736. Epub 2009 Jan 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Animals
  • Collagen Type IV / metabolism
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Enzyme Activation / drug effects
  • Fibronectins / metabolism
  • Glucose / physiology*
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • LLC-PK1 Cells
  • Peptide Fragments / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Protein Tyrosine Phosphatases / metabolism*
  • Signal Transduction / drug effects
  • Swine
  • Transforming Growth Factor beta1 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Collagen Type IV
  • Fibronectins
  • Peptide Fragments
  • Transforming Growth Factor beta1
  • Angiotensin I
  • p38 Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • angiotensin I (1-7)
  • Glucose