Angiotensin II contributes to diabetic renal dysfunction in rodents and humans via notch1/snail pathway

Elena Gagliardini, Norberto Perico, Paola Rizzo, Simona Buelli, Lorena Longaretti, Luca Perico, Susanna Tomasoni, Carla Zoja, Daniela Macconi, Marina Morigi, Giuseppe Remuzzi, Ariela Benigni

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)119-130
Number of pages12
JournalAmerican Journal of Pathology
Volume183
Issue number1
DOIs
Publication statusPublished - Jul 2013

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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