Molecular regulators of collecting duct remodeling

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Sanford Research $350,000 on August 5, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate molecular regulators of collecting duct remodeling and their role in water and ion homeostasis.

The project examines cellular and molecular mechanisms governing the composition and function of the kidney's collecting duct, specifically the balance between principal cells and intercalated cells. The research addresses how changes in this cell type composition contribute to both adaptive responses—such as acid-base homeostasis during alkalosis—and pathological conditions, including acquired nephrogenic diabetes insipidus triggered by lithium treatment for bipolar disorder. The investigators have identified Notch1 and Notch2 signaling via HES1 as required for maintaining aquaporin-2-expressing principal cells, and will use HES1 as a molecular marker to characterize the signature of principal cell-to-intercalated cell conversion. Work is performed in Sioux Falls, South Dakota. The period of performance extends through May 31, 2030.

Abstract

The cellular and molecular mechanisms regulating water and ION homeostasis are important to understand as imbalances in these are frequently associated with kidney disease. Apart from changes in the expression levels of cell type specific water channels and ION channels and transporters, changes in cell type composition within the collecting duct (CD) segments, composed of diverse intermingled principal and intercalated cell types, are associated with disrupted water and ION homeostasis. For example, lithium used to treat bipolar disorder triggers an acquired form of nephrogenic diabetes insipidus (NDI), involving defective reabsorption of water, along with a decrease in ratio of principal cells (PCS) to intercalated cells (ICS). Changes in CD cell type composition are also part of adaptive mechanisms, such as alkalosis, which triggers an increase in pendrin+ IC number to ensure acid-base homeostasis. Based on our observation that PCS can convert into ICS in adult mice, we hypothesize that adjusting CD cell type composition plays a role in adaptive mechanisms to ensure water and electrolyte homeostasis in response to specific diets and is also part of mechanisms that drive pathology such as following lithium treatment. 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 use HES1 as a molecular handle to identify molecular signature of PC to IC conversion and test if PC to IC conversions mediate renal physiology and/or pathology. In specific AIM1, we ask how HES1 suppresses the IC program from turning on in adult PCS and test if this involves suppression of MTORC1 activity using genetic approaches in mice. In specific aim 2 we examine the role of PC to IC interconversions in renal physiology using PC-lineage tracing and IC-lineage tracing mice. We also test if genetically increasing or blocking PC to IC conversions impairs the ability to maintain water and electrolyte homeostasis. In specific AIM3 we will identify mechanisms, independent of suppressing FOXI1, by which notch signaling via HES1 contributes to PC-specific gene expression to impact 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.