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Regulation of Kir4.1/Kir5.1 and renal potassium excretion

Award Number: R01DK136491
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: 07/26/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Regulation of Kir4.1/Kir5.1 and renal potassium excretion - Maintaining K+ homeostasis is essential for the function of heart, skeletal muscles and neurons because hypokalemia or hyperkalemia could cause life-threatening consequence such as cardiac arrhythmia. A recent development in the field has firmly established the role of thiazide-sensitive Na-Cl cotransporter (NCC) in the regulation of K+ homeostasis because the coordinated action among NCC, epithelial Na+ channel (ENaC) and ROMK is essential for maximally enhancing renal K+ excretion (EK) during high dietary K+ intake (HK) and for effectively preventing K+ wasting during low dietary K+ intake (LK). The basolateral Kir4.1 and Kir5.1 channels in the distal convoluted tubule (DCT) play an important role in controlling NCC expression and activity. Our previous studies have demonstrated that HK induced inhibition of Kir4.1/Kir5.1 is an essential step for HK-induced inhibition of NCC. Conversely, LK-induced stimulation of Kir4.1/Kir5.1 of the DCT is an essential step for LK-induced stimulation of NCC. The mechanism by which the basolateral Kir4.1/Kir5.1 in the DCT regulates NCC activity depends on Cl--sensitive with-no-lysine kinase (WNK). The role of Kir4.1 and Kir5.1 in the regulation of renal K+ excretion has been demonstrated in the mouse models: The deletion of Kir4.1 inhibits NCC activity and causes renal K+ wasting, whereas the deletion of Kir5.1 increases NCC activity and reduces renal K+ excretion ability during HK intake. Thus, Kir4.1 and Kir5.1 in the DCT serve as two important members of “potassium-sensor” mechanism. Although the role of Kir4.1/Kir5.1 in regulating NCC and renal K+ excretion is well established, the regulatory mechanism by which dietary K+ intake modulates Kir4.1 and Kir5.1 is not completely understood. We now propose to examine the role of mechanistic target of rapamycin (mTOR) complex 1 (mTORc1) and mTOR complex 2 (mTORc2) in mediating the effect of dietary K+ intake on Kir4.1/Kir5.1 of the DCT. We hypothesize 1) Activation of mTORc1, partially via insulin-like-growth factor 1 (IGF-1), is critically involved in mediating LK-intake-induced stimulation of Kir4.1/Kir5.1 of the DCT and NCC; 2) Activation of mTORc2 inhibits Kir4.1/Kir5.1 by PKC during HK and is involved in HK-intake-induced inhibition of NCC. The proposal has three specific Aims: 1)To test the hypothesis that mTORc1 regulates Kir4.1/Kir5.1 of DCT and NCC under control conditions (normal K+) and plays a role in determining the baseline renal K+ excretion; 2) To test the hypothesis that activation of IGF1-mTORc1 plays a key role in mediating LK-induced stimulation of Kir4.1/Kir5.1 in the DCT and NCC and in suppressing renal K+ excretion; 3) Test the hypothesis that Activation of mTORc2 mediates HK-induced inhibition of Kir4.1/Kir5.1 via PKC and NCC in the DCT thereby enhancing ENaC-dependent renal EK. The significance of our proposal is to explore the novel role of mTORc1/mTORc2 pathways in mediating effects of LK or HK on Kir4.1/Kir5.1, NCC, ENaC and ROMK in the DCT and connecting tubule.


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: 2025 ( Subtotal = $360,800 )
2025	2025	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/15/2025	NON-COMPETING CONTINUATION	$360,800
														Subtotal = $360,800

Issue Date FY: 2024 ( Subtotal = $346,368 )
2024	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/12/2024	NON-COMPETING CONTINUATION	$346,368
														Subtotal = $346,368

Issue Date FY: 2023 ( Subtotal = $360,800 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/24/2023	NEW	$360,800
														Subtotal = $360,800

Grand Total All Awards = $1,067,968

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Regulation of Kir4.1/Kir5.1 and renal potassium excretion

Award Number: R01DK136491

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: 07/26/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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