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Molecular Regulators of Collecting Duct Remodeling

Award Number: R01DK140395
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Molecular Regulators of Collecting Duct Remodeling - PROJECT SUMMARY 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $586,408 )
2026	2026	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/3/2026	NEW	$586,408
														Subtotal = $586,408

Grand Total All Awards = $586,408

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Molecular Regulators of Collecting Duct Remodeling

Award Number: R01DK140395

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/05/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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