Getting a Notch Closer to Understanding Diabetic Kidney Disease
- 1Department of Medicine and Nephrology, Albert Einstein College Medicine, Bronx, New York,
- 2Department of Medicine and Nephrology, Wonkwang University College of Medicine, Iksan, South Korea.
- Corresponding author: Katalin Susztak, .
Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes. Renal dysfunction develops in about one-third of patients with diabetes (1). Diabetic nephropathy is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Current therapies for DKD, including blood glucose control, angiotensin II receptors blockers, and ACE inhibitors, slow down, but do not halt, the progression to end-stage renal disease after overt nephropathy has been established (2). Recent studies indicate that podocyte injury and depletion play key roles in the pathogenesis of DKD (3,4). Clinical observational studies showed a strong correlation between podocyte density, albuminuria and renal function decline in patients with type 1 and type 2 diabetes (5).
Notch signaling regulates many aspects of metazoan development and tissue renewal (6). Notch is a transmembrane protein that interacts with ligands of the Jagged and Delta family (7). In mammals, there are four Notch receptors (Notch 1–4), two Jaggeds, and three delta-like ligands (8). Each of these proteins show a cell type- and tissue-specific expression. Notch is made in the endoplasmic reticulum as pre-Notch. A furin-like convertase cleaves pre-Notch to intracellular and extracellular domain. The protein is then transported to the plasma membrane. Interaction of the ligand with the Notch receptor triggers a series of proteolytic cleavage, by ADAM, a disintegrin and metalloprotease and by the γ-secretase complex. The final cleavage releases the Notch intracellular domain (NICD), which then moves to the nucleus, where it can regulate gene …