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Functional characterization of a novel key regulator of the distal nephron whose deficiency leads to renal fibrosis and cyst formation

Award Number: R01DK118134
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY: The distal nephron epithelium acquires essential functions for urinary concentration during its maturation phase following nephrogenesis. We identified KCTD1 as a critical regulator of the maturation and function of the thick ascending limb (TAL) and the distal convoluted tubule (DCT) of the distal nephron. KCTD1 deficiency leads to impaired maturation of these nephron segments with loss of key electrolyte transporters, resulting in an early-onset severe salt-losing tubulopathy and a delayed-onset nephronophthisis-like cyst formation and kidney fibrosis. Mechanistically, lack of KCTD1 increases expression of the epithelial differentiation regulator DAPL1, which we propose suppresses maturation and terminal differentiation of the distal nephron epithelium by increasing ß-catenin signaling activity through inhibition of the expression of the Wnt inhibitor SFRP1. Inhibiting the increase in ß-catenin activity in mice lacking KCTD1 prevented the loss of electrolyte transporters, improved kidney function and attenuated fibrosis and cyst formation. Thus, KCTD1 controls distal nephron maturation and function by suppressing postnatal ß-catenin activation. In this proposal we aim to define the molecular mechanisms through which KCTD1 controls DAPL1 expression and Wnt/b¿-catenin signaling activity in the distal nephron epithelium and thereby affects the differentiation and function of this epithelium. Our new preliminary data show that increased AP-2a¿ in the TALs/DCTs of mice lacking KCTD1 is required for the increase in Wnt/ß-catenin signaling in these TALs/DCTs and that lack of AP- 2a¿ can rescue the distal nephron maturation defects caused by KCTD1 deficiency. Based on these findings we hypothesize that KCTD1 acts in the TALs/DCTs as an inhibitor of the transcription factor AP-2a¿, which induces the expression of DAPL1. We will test this hypothesis and explore how AP-2a¿ controls DAPL1 expression and whether the functions of KCTD1 for distal nephron maturation are mediated by AP-2a¿ and DAPL1. Moreover, we will test whether DAPL1 stimulates Wnt/b¿-catenin signaling activity in the TALs/DCTs by inhibiting the expression of SFRP1 and define the molecular regulation and in vivo significance of a KCTD1/AP- 2a¿/DAPL1/SFRP1 axis in controlling Wnt/ß-catenin signaling activity and maturation and function of the distal nephron epithelium. The scientific premise for this application is strong and builds on extensive preliminary data, mouse models that have already been generated and verified in our laboratory, and a primary human TAL/DCT cell culture system for which the feasibility of the proposed experiments has been clearly established by our preliminary data. The proposed experiments are expected to provide fundamental new insights into molecular mechanisms that control the maturation and terminal differentiation of the TALs/DCTs. Thus, this proposal has high translational significance in defining a previously unexplored molecular pathway that is critical for distal nephron function and may provide novel therapeutic targets for kidney diseases with TAL/DCT dysfunction.


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: 2023 ( Subtotal = $349,872 )
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/15/2022	NON-COMPETING CONTINUATION	$314,885
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	1/11/2023	NON-COMPETING CONTINUATION	$34,987
														Subtotal = $349,872

Issue Date FY: 2022 ( Subtotal = $349,872 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/4/2022	NON-COMPETING CONTINUATION	$34,988
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/19/2021	NON-COMPETING CONTINUATION	$314,884
														Subtotal = $349,872

Issue Date FY: 2021 ( Subtotal = $349,872 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/2/2021	NON-COMPETING CONTINUATION	$34,988
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/20/2020	NON-COMPETING CONTINUATION	$314,884
														Subtotal = $349,872

Issue Date FY: 2020 ( Subtotal = $349,872 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/28/2019	NON-COMPETING CONTINUATION	$314,884
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	2/21/2020	NON-COMPETING CONTINUATION	$34,988
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/27/2019	NEW	$0
														Subtotal = $349,872

Issue Date FY: 2019 ( Subtotal = $349,872 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/20/2018	NEW	$349,872
														Subtotal = $349,872

Grand Total All Awards = $1,749,360

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Functional characterization of a novel key regulator of the distal nephron whose deficiency leads to renal fibrosis and cyst formation

Award Number: R01DK118134

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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