title: Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Elisandra
authors.initials: E
authors.lastname: Gava
authors.forename: Arman
authors.initials: A
authors.lastname: Samad-Zadeh
authors.forename: Joseph
authors.initials: J
authors.lastname: Zimpelmann
authors.forename: Nasim
authors.initials: N
authors.lastname: Bahramifarid
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Kitten
authors.forename: Robson A
authors.initials: RA
authors.lastname: Santos
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose / Q000502:physiology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D010446:Peptide Fragments; D053773:Transforming Growth Factor beta1; D000803:Angiotensin I; D048051:p38 Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C118790:angiotensin I (1-7); D005947:Glucose