![]() Global Notch3 and Notch4 knockout animals are viable with minimal, if any, phenotypic changes. The variable severity of developmental defects resulting from loss of different Notch receptors or ligands further illustrates that, despite utilization of the same signaling architecture, these are not redundant genes. Notch has an important role in kidney development. ![]() NOTCH ACTIVITY IS CRITICAL FOR KIDNEY DEVELOPMENT These features give the Notch pathway a unique and critical role in distinguishing cell types and deciding cell fates during development, differentiation, and disease pathogenesis. Both types of signaling result in segregated cell populations by establishing boundaries between homogeneous cell types and/or developing heterogeneous cell populations within tissues. The cell containing the Notch receptor directs neighboring cells to either inhibit Notch ligand/receptor expression (lateral inhibition) or to establish a small population of adjacent Notch signaling cells (inductive signaling). Notch signaling requires the interaction of at least two different cell types. When compared with other signaling pathways, several unique features of Notch signaling become apparent. Whether or how resultant signaling differs with engagement of one ligand over another is still undergoing evaluation in the field. For example, modification of Notch by manic fringe confers an increased affinity for Dll1 and a decreased affinity for Jag1, essentially allowing Dll1 to outcompete Jag1 for the Notch receptor. 5, 6 O-fucosylation or O-glycosylation via fringe proteins (lunatic, radical, and manic) regulates the specificity of Notch receptor-ligand binding. Post-translational modification of Notch is equally critical for its function. 4 Although altered expression of the Hey/Hes genes are occasionally reported independently of Notch, their expression patterns are consistent enough to be routinely utilized as proof-of-function for Notch signaling. Hey and Hes operate primarily as repressive transcription factors. The most commonly recognized Notch target genes are the helix-loop-helix proteins of the Hey/Hes family. The intracellular part, known as the Notch intracellular domain (NICD), translocates to the nucleus where it complexes with transcription cofactors, such as RBPj and Mastermind-like proteins, to alter gene expression. The extracellular cleavage product remains bound to the ligand-presenting cell to be endocytosed. 3 The Notch protein is proteolytically cleaved on the extracellular face by ADAM/TACE proteases and on the intracellular side of the plasma membrane by γ-secretase. 2 The canonical Notch signaling pathway is initiated when the extracellular domain of a Notch receptor binds to a Notch ligand in a trans-interaction (receptor and ligand on opposite cells). In mammals, there are four Notch receptors (Notch 1–4) and two classes of canonical ligands, Jagged (Jag1, 2) and Delta-like ligand (Dll1, 3, and 4). Here, we will examine kidney fibrosis and Notch signaling with respect to the renal epithelial cell. For example, genetic manipulation of the signaling pathway only in epithelial cells has a profound effect on interstitial fibrosis development. Mouse models further support the role of epithelial cells in interstitial fibrosis development. As the primary functions of the kidney (filtration, reabsorption, and secretion) are performed by epithelial cells, we believe that the loss of functional epithelium and tubular atrophy must be the most critical contributors to loss of renal function. However, the key process that causes the functional decline of the kidney is unclear. These fibrotic changes in the intersitium (termed ‘interstitial fibrosis') are currently used as critical pathologic diagnostic criteria in determining the severity of CKD. For example, capillary rarefaction will cause tubular atrophy, and loss of tubular epithelial cells will further fuel further capillary loss. As the functions of different cell types are interrelated in the kidney, these events will feed into each other as the fibrosis progresses. Different insults can initiate fibrosis, such as epithelial injury, persistent inflammation, or progressive capillary loss. ![]() Kidney fibrosis is characterized by five distinct changes: glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary loss, and inflammation. 1 Histological lesions that are associated with CKD are collectively described as fibrosis. The terms ‘chronic kidney disease' (CKD) and its most severe form, ‘end-stage renal disease', describe the progressive functional decline of the kidney. ![]()
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