title: Angiotensin-(1-7) abolishes AGE-induced cellular hypertrophy and myofibroblast transformation via inhibition of ERK1/2.
abstract: Angiotensin-(1-7) (Ang-(1-7))/AT7-Mas receptor axis is an alternative pathway within the renin-angiotensin system (RAS) that generally opposes the actions of Ang II/AT1 receptor pathway. Advanced glycated end product (AGEs) including glucose- and methylglyoxal-modified albumin (MGA) may contribute to the development and progression of diabetic nephropathy in part through activation of the Ang II/AT1 receptor system; however, the influence of AGE on the Ang-(1-7) arm of the RAS within the kidney is unclear. The present study assessed the impact of AGE on the Ang-(1-7) axis in NRK-52E renal epithelial cells. MGA exposure for 48 h significantly reduced the intracellular levels of Ang-(1-7) approximately 50%; however, Ang I or Ang II expression was not altered. The reduced cellular content of Ang-(1-7) was associated with increased metabolism of the peptide to the inactive metabolite Ang-(1-4) [MGA: 175±9 vs.
  
  
  METHODS
  115±11 fmol/min/mg protein, p<0.05, n=3] but no change in the processing of Ang I to Ang-(1-7). Treatment with Ang-(1-7) reversed MGA-induced cellular hypertrophy and myofibroblast transition evidenced by reduced immunostaining and protein expression of α-smooth muscle actin (α-SMA) [0.4±0.1 vs. 1.0±0.1, respectively, n=3, p<0.05]. Ang-(1-7) abolished AGE-induced activation of the MAP kinase ERK1/2 to a similar extent as the TGF-β receptor kinase inhibitor SB58059; however, Ang-(1-7) did not attenuate the MGA-stimulated release of TGF-β. The AT7-Mas receptor antagonist D-Ala(7)-Ang-(1-7) abolished the inhibitory actions of Ang-(1-7). In contrast, AT1 receptor antagonist losartan did not attenuate the MGA-induced effects. We conclude that Ang-(1-7) may provide an additional therapeutic approach to the conventional RAS blockade regimen to attenuate AGE-dependent renal injury.
authors.affiliation: The Hypertension & Vascular Disease Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
authors.forename: Ebaa M
authors.initials: EM
authors.lastname: Alzayadneh
authors.affiliation: The Hypertension & Vascular Disease Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA. Electronic address: mchappel@wfubmc.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D000418:Albumins / Q000633:toxicity; D000803:Angiotensin I / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D006984:Hypertrophy; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000418:Albumins; D017127:Glycation End Products, Advanced; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D000803:Angiotensin I; D048049:Extracellular Signal-Regulated MAP Kinases; C118790:angiotensin I (1-7)
keywords: Advanced glycation endproducts; Angiotensin; EMT; ERK1/2; TGF-B