title: Angiotensin II activation of mTOR results in tubulointerstitial fibrosis through loss of N-cadherin.
abstract: OBJECTIVE
  Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis.
  
  
  METHODS
  We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT(1)R) blocker telmisartan (2 mg · kg(-1) · day(-1)) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function.
  
  
  RESULTS
  Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine(2448) phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats.
  
  
  CONCLUSIONS
  Our observations suggest that Ang II activation of the AT(1)R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.
authors: Harry S. Truman VA Medical Center, and the University of Missouri-Columbia School of Medicine, USA. whaleyconnella @ health.missouri.edu
authors: Adam
authors: A
authors: Whaley-Connell
authors: Javad
authors: J
authors: Habibi
authors: Zachary
authors: Z
authors: Panfili
authors: Melvin R
authors: MR
authors: Hayden
authors: Sarika
authors: S
authors: Bagree
authors: Ravi
authors: R
authors: Nistala
authors: Safwan
authors: S
authors: Hyder
authors: Bennett
authors: B
authors: Krueger
authors: Vincent
authors: V
authors: Demarco
authors: Lakshmi
authors: L
authors: Pulakat
authors: Carlos M
authors: CM
authors: Ferrario
authors: Alan
authors: A
authors: Parrish
authors: James R
authors: JR
authors: Sowers
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D005355:Fibrosis / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008871:Microvilli / Q000378:metabolism; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015820:Cadherins; C535029:Ren2 protein, rat; D000804:Angiotensin II; D019255:NADPH Oxidases; D058570:TOR Serine-Threonine Kinases; D012083:Renin