Notch signaling during kidney development and injury responses

Mammalian Notch receptors (Notch 1-4) regulate cellular differentiation during organ development and Notch receptors and their ligands are expressed in the developing kidney.;Notch signaling may control the fate of renal epithelial stem cells (RESCs) during kidney development. To test this hypothesis, conditional knockouts of the Recombination binding protein for immunoglobulin kappa j-region (Rbp-j), a transcription factor required for Notch signaling, were generated. Rbp-j deletion was directed to the kidney using Cre-expressing strains that are active at specific stages of nephrogenesis. Rbp-j mutation in RESCs caused renal hypoplasia and severely disrupted proximal tubule development. The few nephrons that formed were mosaic and contained both Rbp-j knockout cells and cells that had escaped Cre-mediated Rbp-j recombination. Rbp-j knockout cells were seen in glomerular and distal tubular epithelia but not in normal proximal tubules. In contrast to the role of Notch signaling in RESCs, deletion of Rbp-j in podocytes, after their fate as glomerular epithelial cells has been established, did not disturb glomerular maturation or function. Together these data suggest that Notch signaling is required to pattern the renal vesicle and initiate nephron development and thereafter is only required for the formation of proximal tubules.;Notch4 is expressed in the glomerulus but unlike conditional knockouts of Rbp-j, Notch4 knockout (Notch4 -/-) mice have normal kidney function at birth. I hypothesized that Notch4-deficiency may confer susceptibility to glomerular injury and so induced nephritis in congenic Notch4-/- and wild-type mice using a model known to be dependent on cell-mediated immunity. Surprisingly, nephritis was ameliorated in Notch4-/- mice but not in mice with conditional mutation of Rbp-j in podocytes. Macrophages and antigen presenting cells were found to express Notch4 and Notch4-deficiency decreased inflammatory cell infiltration into the nephritic kidney. Thus, Notch4 deficiency protected against cell-mediated glomerular injury.;In conclusion, Notch signaling is required for tubulogenesis of the proximal tubule but is not necessary for the specification of distal tubules or podocytes. An unexpected role for Notch4 in immune-mediated glomerular injury was discovered that may be explained by altered cellular immunity rather than by changes in the injury responses of glomerular cells.