Angiotensin II contributes to diabetic renal dysfunction in rodents and humans via Notch1/Snail pathway.

Abstract

In nondiabetic rat models of renal disease, angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. Herein, we wanted to explore the role of Ang II in diabetic nephropathy by a translational approach spanning from in vitro to in vivo rat and human studies, and to dissect the intracellular pathways involved. In isolated perfused rat kidneys and in cultured human podocytes, Ang II down-regulated nephrin expression via Notch1 activation and nuclear translocation of Snail. Hairy enhancer of split-1 was a Notch1-downstream gene effector that activated Snail in cultured podocytes. In vitro changes of the Snail/nephrin axis were similar to those in renal biopsy specimens of Zucker diabetic fatty rats and patients with advanced diabetic nephropathy, and were normalized by pharmacological inhibition of the renin-angiotensin system. Collectively, the present studies provide evidence that Ang II plays a relevant role in perpetuating glomerular injury in experimental and human diabetic nephropathy via persistent activation of Notch1 and Snail signaling in podocytes, eventually resulting in down-regulation of nephrin expression, the integrity of which is crucial for the glomerular filtration barrier.

• Authors: Elena Gagliardini, Norberto Perico, Paola Rizzo, Simona Buelli, Lorena Longaretti, Luca Perico, Susanna Tomasoni, Carla Zoja, Daniela Macconi, Marina Morigi, Giuseppe Remuzzi, Ariela Benigni
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 1 Pg. 119-30 (Jul 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23707238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• NOTCH1 protein, human
• Notch1 protein, rat
• Receptor, Notch1
• Snai2 protein, rat
• Snail Family Transcription Factors
• Transcription Factors
• nephrin
• Angiotensin II

Topics

• Aged
• Angiotensin II (metabolism)
• Animals
• Case-Control Studies
• Cells, Cultured
• Diabetes Mellitus, Type 2 (complications)
• Diabetic Nephropathies (metabolism)
• Down-Regulation
• Female
• Humans
• Immunohistochemistry
• Kidney (metabolism, pathology)
• Linear Models
• Male
• Membrane Proteins (metabolism)
• Microscopy, Electron, Transmission
• Middle Aged
• Rats
• Rats, Sprague-Dawley
• Rats, Zucker
• Real-Time Polymerase Chain Reaction
• Receptor, Notch1 (metabolism)
• Snail Family Transcription Factors
• Transcription Factors (metabolism)