Article abstract
Nature Medicine 14, 290 - 298 (2008)
Published online: 2 March 2008 | doi:10.1038/nm1731
The Notch pathway in podocytes plays a role in the development of glomerular disease
Thiruvur Niranjan1, Bernhard Bielesz1, Antje Gruenwald1, Manish P Ponda1, Jeffrey B Kopp2, David B Thomas3 & Katalin Susztak1
Abstract
Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a 
-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.
- Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461, USA.
- Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Room 3N116, Bethesda, Maryland 20892-1268, USA.
- Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461, USA.
Correspondence to: Katalin Susztak1 e-mail: ksusztak@aecom.yu.edu