Wednesday, January 21, 2026 1/21/2026

Regulation of NKCC2 and renal NaCl transport by protein-protein interactions

Award Number: R01DK131114
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: 01/20/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

Regulation of NKCC2 and renal NaCl transport by protein-protein interactions - Abstract In the kidney, the thick ascending limb (TAL) of the loop of Henle is critical for NaCl homeostasis and blood pressure regulation. In humans and animal models of salt-sensitive hypertension, NaCl absorption is abnormally increased in the TAL, where NaCl absorption depends on the renal transporter NKCC2, an apical Na+/K+/2Cl- co-transporter. We showed that the presence of NKCC2 at the TAL apical membrane controls NaCl absorption in this epithelium. The molecular mechanisms that control apical membrane NKCC2 levels involve endocytosis, recycling and exocytic insertion. Inhibition of endocytic retrieval causes NKCC2 accumulation at the membrane and increased NaCl absorption. Any gene or protein affecting NKCC2 endocytosis could potentially influence NKCC2 activity and renal salt transport but only few proteins are known to bind NKCC2. Using a targeted proteomics screen, we identified ALMS1 (Alström Syndrome 1) and ACTN4 (alpha-actinin 4) as interacting partners of NKCC2. We also found that ALMS1 and ACTN4 interact with each other, raising the possibility that these proteins form a complex. Single nucleotide polymorphisms in ALMS1 and ACTN4 are associated with hypertension and decreased kidney function. We found that ALMS1 knockout rats have higher surface NKCC2 and high blood pressure. We found that ACTN4, a protein involved in podocyte biology, is also expressed throughout the nephron, including the TAL. The roles of ALMS1 and ACTN4 in renal NaCl handling by the TAL and their role in blood pressure regulation are unknown. We hypothesize that ALMS1 controls surface NKCC2 levels and NKCC2-mediated NaCl absorption by binding the carboxyl-terminus of NKCC2 and ACTN4 to mediate NKCC2 endocytosis from the apical membrane. A decrease in ALMS1 or ACTN4 expression in the TAL increases surface NKCC2, NKCC2-mediated NaCl reabsorption, tubulo-glomerular feedback (TGF) sensitivity and leads to salt-sensitive hypertension. Our long-term goal is to increase our understanding of the role of ALMS1 and ACTN4 in kidney NaCl transport.


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 = $559,687 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$559,687
														Subtotal = $559,687

Issue Date FY: 2025 ( Subtotal = $484,984 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/23/2024	NON-COMPETING CONTINUATION	$484,984
														Subtotal = $484,984

Issue Date FY: 2024 ( Subtotal = $583,354 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/20/2024	NON-COMPETING CONTINUATION	$36,458
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/28/2023	NON-COMPETING CONTINUATION	$546,896
														Subtotal = $583,354

Issue Date FY: 2023 ( Subtotal = $602,240 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/20/2023	NEW	$602,240
														Subtotal = $602,240

Grand Total All Awards = $2,230,265

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Regulation of NKCC2 and renal NaCl transport by protein-protein interactions

Award Number: R01DK131114

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: 01/20/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer