Developmental anomalies account for 40% of chronic renal failure in children under age 4. In adults, the kidney is a major collateral target organ of disease processes and drug toxicity. In addition, cardiovascular homeostasis depends on precise regulation of blood pressure and electrolyte balance, neither of which can be maintained without good renal function; therefore, identifying the molecular regulators of kidney development and regeneration are of critical importance to human health. Many signals (GDNF, LIF, FGF-2, TGFbeta, Wnt-4, and Notch) control nephron development and, not surprisingly, many are arranged in feedback loops, such that signal integration maintains the balance of signaling necessary for the differentiation and development of multiple renal cell types that compose the adult kidney. Fully elucidating the role of Notch signaling in kidney development and its integration with other signaling pathways is of great importance. The genetic evidence in support of a role for Notch signaling is that partial loss of the Notch ligand Jagged I affects kidney function in humans (Alagille-Syndrome) and hypomorphic mutations in Notch-2 impair glomemlar development in mice. Despite these excellent studies, the role of the Notch pathway during all stages of renal development is under-investigated due to early embryonic lethality and redundancy of Notch receptors. The dependence of all Notch receptor activation on proteases and the selectivity of DAPT for presenilin-dependent protease (7-secretase) permit us to pharmacologically manipulate Notch signaling in an organ culture system, circumventing lethality. Our experiments uncovered a requirement for Notch signaling operating at an earlier time during kidney development than was previously appreciated: we discovered that 7-secretase activity (and thus Notch signaling) is essential for specification of proximal epithelial cell fates (podocyte and proximal tubule); a role for Notch in this process suggests a possible role in kidney regeneration post injury in adults, where Notch and its ligands are up-regulated in a renal fibrosis model. This application Specific Aims to identify Notch-dependent processes and downstream Notch targets during development and during adult kidney regeneration in several renal injury models.
Showing the most recent 10 out of 30 publications
