Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function

Recent studies indicate that the Notch signaling pathway plays an important role in the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we analyzed the degree of expression and localization of Notch ligands (Jagged1 and Delta1) and activated (cleaved) receptors (Notch1 and Notch2) in healthy human kidneys and in renal biopsies from a wide variety of kidney diseases. These included patients with minimal change disease, membranous nephropathy, lupus nephritis ISN/RPS classes III/IV/V, hypertensive nephrosclerosis, crescentic glomerulonephritis, tubulointerstitial fibrosis, IgA nephropathy, diabetic kidney disease, and FSGS. We found that cleaved Notch1, Notch2, and Jagged1 are expressed on podocytes in proteinuric nephropathies and their level of expression correlated with the amount of proteinuria across all disease groups. The degree of glomerulosclerosis correlated with podocyte expression of cleaved Notch1, while the severity of tubulointerstitial fibrosis and the estimated glomerular filtration rate correlated with expression of cleaved Notch1 in the tubulointerstitium. Hence, our results raise the possibility that Notch pathway activation is a common mechanism in the pathophysiology of a wide range of acquired renal diseases.