Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY: It is critical to understand the cellular and molecular mechanisms regulating water and ion homeostasis, as imbalances in these are frequently associated with kidney disease. While mutations in ion and water channels and in regulators of these channels, result in congenital forms of fluid and electrolyte disorders, the cellular and molecular basis of acquired forms of fluid and electrolyte imbalances are less clear. Changes in ratios of kidney epithelial cell types within distal nephron and collecting duct (CD) segments, composed of diverse intermingled principal and intercalated cell types, have been correlated with the occurrence of water and electrolyte disorders. For example, lithium treatment of patients with bipolar disorder triggers an acquired form of nephrogenic diabetes insipidus (NDI), involving an inability to sufficiently reabsorb water, along with a decrease in ratio of principal cells (PCs) to intercalated cells (ICs). To understand the relationship of cell type changes to water and ion homeostasis we have identified that Notch1&2 signaling via Hes1 is required for maintaining Aquaporin-2 (Aqp2) expressing PCs in the distal nephron, and CD segments of adult mouse kidneys, without which the PCs are replaced with ICs. We identified Elf5 to be a PC specific marker downstream of Notch signaling and used Elf5- lineage tracing mice to monitor the fate of mature PCs in adult kidneys. Interestingly, either inhibition of Notch signaling or short-term lithium treatment promotes mature PCs to convert into ICs. Here we propose to test the hypothesis that PC to IC conversion contributes to water reabsorption defect in acquired NDI, while IC to PC conversion are important in the recovery from NDI. The overarching novel hypothesis is that Notch1&2 via Hes1 regulate water and ion homeostasis in PCs by directly regulating expression and/or function of water and ion channels independent of preventing PCs to switch into ICs. However, in response to certain diets or mediations Notch signaling is pathologically suppressed and triggers PC to IC conversions resulting in NDI. To test this hypothesis and to understand the mechanisms by which PC to IC conversions occur, and importance of PC to IC conversions to acquired forms of NDI we propose three specific aims. In Specific Aim1, we ask how Hes1 does suppress the IC program from turning on in adult PCs? In this aim we will examine the mechanisms regulating PC to IC conversions. In Specific Aim2 we will identify mechanisms, independent of suppressing Foxi1, by which Notch signaling contributes to PC functions. This will test whether Notch signaling is part of the principal cell signaling network that responds to physiologic stimuli such as aldosterone, and hyperosmolality. In specific aim 3 we will determine if acquired NDI involves PC to IC conversions and test if IC to PC conversions are part of the regenerative capacity of the kidney to recover from NDI.
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