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 γ-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.
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We thank T. Honjo (Kyoto University) for providing the Rbpjflox mice, D. Melton (Harvard University) and B. Stanger (University of Pennsylvania) for providing the tetO-ICN1 mice, P. Mundel (Mount Sinai School of Medicine) for providing the conditionally immortalized podocyte cell line, W. Pear (University of Pennsylvania) for providing the ICN1/EGFP-MIGR retroviral construct, L. Holzman (University of Michigan) for providing the podocin-cre mice and the antibody to nephrin, and A. Biser for technical assistance. We thank the Analytical Imaging Facility at Albert Einstein College of Medicine for electron microscopy. This work was supported by 1R01DK076077 (US National Institute of Diabetes and Digestive and Kidney Diseases) and by the Carl Gottschalk Award of the American Society of Nephrology to K.S.
The Albert Einstein College of Medicine of Yeshiva University has filed a patent application covering aspects of this research.
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Niranjan, T., Bielesz, B., Gruenwald, A. et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 14, 290–298 (2008) doi:10.1038/nm1731
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