The Notch pathway in podocytes plays a role in the development of glomerular disease.
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 gamma-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.
Niranjan
Thiruvur
T
Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461, USA.
Bielesz
Bernhard
B
Gruenwald
Antje
A
Ponda
Manish P
MP
Kopp
Jeffrey B
JB
Thomas
David B
DB
Susztak
Katalin
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003928:Diabetic Nephropathies / Q000378:metabolism*; D003984:Dibenzazepines / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009281:Naphthalenes; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011725:Pyridines; D051381:Rats; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D003984:Dibenzazepines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009281:Naphthalenes; D011725:Pyridines; D051880:Receptors, Notch; D053773:Transforming Growth Factor beta1; C495514:naphthalene-(1,2'-pyridylazo)-2-naphthol; C527817:dibenzazepine