Angiotensin II activation of mTOR results in tubulointerstitial fibrosis through loss of N-cadherin.

Abstract

BACKGROUND/AIMS:

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: Adam Whaley-Connell, Javad Habibi, Zachary Panfili, Melvin R Hayden, Sarika Bagree, Ravi Nistala, Safwan Hyder, Bennett Krueger, Vincent Demarco, Lakshmi Pulakat, Carlos M Ferrario, Alan Parrish, James R Sowers
• Journal: American journal of nephrology (Am J Nephrol) Vol. 34 Issue 2 Pg. 115-25 ( 2011) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 21720156 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 S. Karger AG, Basel.

Chemical References

• Cadherins
• Ren2 protein, rat
• Angiotensin II
• NADPH Oxidases
• TOR Serine-Threonine Kinases
• Renin

Topics

• Angiotensin II (metabolism)
• Animals
• Animals, Genetically Modified
• Cadherins (metabolism)
• Cell Adhesion
• Fibrosis (metabolism)
• Male
• Microscopy, Electron, Transmission (methods)
• Microvilli (metabolism)
• Models, Biological
• NADPH Oxidases (metabolism)
• Oxidative Stress
• Rats
• Rats, Sprague-Dawley
• Renin (genetics)
• TOR Serine-Threonine Kinases (metabolism)