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Fructose induced salt-sensitive hypertension: Role of thick ascending limb transport

Award Number: R01DK107263
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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¿ DESCRIPTION (provided by applicant): A high-fructose diet is linked to the epidemic of hypertension, diabetes, and obesity. Up to 25 million Americans consume up to 20% of their calories from added fructose1, 2. We found that feeding rats a fructose-enriched diet (20%) for 4 weeks did not increase blood pressure. However, a fructose-enriched diet combined with high salt (4% Na) caused salt-sensitive hypertension within 1 week (Figures 1, 11); prior to the development of metabolic abnormalities. The initial phase of salt-sensitive hypertension is in part mediated by a renal defect that prevents NaCl excretion during high salt intake. The thick ascending limb (TAL) reabsorbs 25% of filtered NaCl. Enhanced TAL NaCl absorption is related to salt-sensitive hypertension in humans and rodents3-5. However, the mechanism by which a fructose-enriched diet rapidly (1 week) causes salt-sensitive hypertension is not clear and the role of TAL NaCl absorption in this process is completely unknown. NaCl reabsorption by the TAL depends on the apical Na/K/2Cl cotransporter NKCC2, the target of loop diuretics. Our preliminary data show that a fructose-enriched diet enhanced NKCC2 phosphorylation at Threonine (Thr) 96,101. NKCC2 phosphorylation at Thr96, 101 activates NKCC26, 7. Our data show that NKCC2-mediated NaCl transport is abnormally elevated in rats fed fructose plus a high salt diet. However, the effects of fructose and the signaling induced in the TAL and the distal nephron have not been studied. Our data show that plasma and urine fructose increase rapidly after fructose intake. Thus, fructose reaching the nephron may be transported in by a fructose channel, activating protein kinase signaling. The only kinases known to phosphorylate Thr96, 101 of NKCC2 are SPAK (STE20/SPS1-related proline-alanine-rich kinase) and OSR1 (Oxidative Stress Responsive 1) kinases. In the TAL, these kinases specifically phosphorylate NKCC2. In the distal convoluted tubule (DCT), these kinases specifically phosphorylate the thiazide-sensitive NaCl transporter NCC. We found that a 20% fructose diet increases SPAK/OSR1 phosphorylation in TALs. In addition, stimulation of ß-adrenergic receptors (ß-AR) in the TAL activates NKCC213. A fructose-enriched diet may increase sympathetic activity by 2 weeks12, or enhance the sensitivity or signaling of ß-AR. Our preliminary data show that ß-AR stimulation increases SPAK/OSR1 phosphorylation in TALs. In the Dahl salt sensitive (SS) rat, NKCC2 and SPAK/OSR1 phosphorylation are abnormally enhanced in a normal salt diet. It is not known whether this increases the effect of fructose on blood pressure and NaCl absorption. We hypothesize that a fructose-enriched diet enhances thick ascending limb (TAL) and distal tubule (DCT) NaCl absorption by inducing NKCC2 and NCC phosphorylation via SPAK/OSR1 kinases and enhanced ß-AR signaling. These effects occur within 1 week, prior to metabolic alterations, and are maintained chronically (16 weeks), promoting salt-sensitive hypertension in normal rats. In Dahl SS rats, abnormally elevated SPAK/OSR1 in the TAL, enhances the effect of fructose on blood pressure in normal- or high-salt diets.


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 = $0 )
2023	2020	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $400,968 )
2020	2020	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/24/2020	NON-COMPETING CONTINUATION	$400,968
														Subtotal = $400,968

Issue Date FY: 2019 ( Subtotal = $400,968 )
2019	2019	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/24/2019	NON-COMPETING CONTINUATION	$400,968
														Subtotal = $400,968

Issue Date FY: 2018 ( Subtotal = $455,716 )
2018	2018	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/18/2018	NON-COMPETING CONTINUATION	$455,716
														Subtotal = $455,716

Issue Date FY: 2017 ( Subtotal = $422,829 )
2017	2017	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/17/2017	NON-COMPETING CONTINUATION	$422,829
														Subtotal = $422,829

Issue Date FY: 2016 ( Subtotal = $452,687 )
2016	2016	HENRY FORD HEALTH SYSTEM	2799 WEST GRAND BOULEVARD	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/15/2016	NEW	$452,687
2016	2016	HENRY FORD HEALTH SYSTEM	2799 WEST GRAND BOULEVARD	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/18/2016	NEW	$0
														Subtotal = $452,687

Grand Total All Awards = $2,133,168

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Fructose induced salt-sensitive hypertension: Role of thick ascending limb transport

Award Number: R01DK107263

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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