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Novel Roles and Mechanisms of Proximal Tubule Mitochondrial Angiotensin II and Sirtuin 3 in Hypertension

Award Number: R01DK067299
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Novel Roles and Mechanisms of Proximal Tubule Mitochondrial Angiotensin II and Sirtuin 3 in Hypertension - Hypertension is a major risk factor for stroke, cardiovascular and kidney injury with nearly 50% of the US adults develop hypertension and take antihypertensive drugs daily. However, the mechanisms underlying the development of hypertension and kidney injury remain incompletely understood. During the last funding period, we demonstrated two functional mitochondrial angiotensin II (Ang II)/Agtr1a/O2- and Ang II/Agtr2/NO/cGMP signaling pathways in the proximal tubules that play key counteracting roles in regulating mitochondrial function, inducing mitochondrial dysfunction, and Ang II- induced hypertension. The proximal tubules are a key player in Ang II-induced hypertension and ischemia and reperfusion (I/R)-induced kidney injury (AKI), because the proximal tubules reabsorb >65% of the filtered NaCl from the glomeruli and are extremely sensitive to mitochondrial dysfunction in hypertension and I/R-induced AKI. Sirtuin 3 (SIRT3), a NAD- dependent deacetylase, is a major mitochondrial protein in the matrix that is encoded by the SIRT3 gene. The key functions of SIRT3 in the mitochondria include important anti-oxidative, anti-inflammation, and blood pressure-lowering effects by decreasing reactive oxygen species/O2- production via activation of long chain fatty acyl-CoA dehydrogenase (LCAD), succinate dehydrogenase (SDH), and NADH dehydrogenase. Ang II induces mitochondrial dysfunction by inhibiting SIRT3 expression and increasing O2- production which contributes to hypertension and AKI. Moreover, SIRT3 has been implicated in sex dimorphism in Ang II-induced hypertension and I/R-induced AKI, with premenopausal females expressing higher levels of SIRT3 and more protective against the development of hypertension and AKI. However, whether SIRT3 in the mitochondria of the proximal tubules plays an important sex-specific role in Ang II-induced hypertension and I/R-induced AKI has not been studied previously. In preliminary studies, we have demonstrated for the 1st time that deletion of SIRT3 selectively in the mitochondria of the proximal tubules augments, whereas overexpression of a mitochondria-targeting SIRT3 in the proximal tubules attenuates, Ang II-induced hypertension and I/R-induced AKI in a novel proximal tubule- specific PT-Sirt3-/- mouse model. In this revised R01 renewal proposal, we will mechanistically test this new hypothesis using novel proximal tubule-specific, mitochondria-targeting loss and gain of function in proximal tubule cell and mutant mouse models. Specific Aim 1 will determine whether deletion of SIRT3 in the mitochondria of the proximal tubules will aggravate Ang II-induced and 2-kidney, 1-clip (2K1C) Goldblatt hypertension, whereas overexpression of SIRT3 in the mitochondria of the proximal tubules will attenuate Ang II-induced and 2K1C Goldblatt hypertension. Specific Aim 2 will determine whether deletion of SIRT3 selectively in the mitochondria of the proximal tubules will aggravate I/R-induced AKI, whereas overexpression of SIRT3 selectively in the mitochondria of the proximal tubules will attenuate I/R-induced AKI. Finally, Specific Aim 3 will mechanistically elucidate the molecular and signaling mechanisms underlying the detrimental effects of deletion and beneficial effects of overexpression of SIRT3 selectively in the mitochondria of mouse proximal tubule cells. This project will help uncover new mechanisms of Ang II-induced hypertension and AKI and develop novel proximal tubule-specific, mitochondria-targeting therapeutic drugs to treat poorly controlled hypertension and AKI.


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 = $706,360 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	5/5/2026	NON-COMPETING CONTINUATION	$706,360
														Subtotal = $706,360

Issue Date FY: 2025 ( Subtotal = $706,588 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	8/5/2025	COMPETING CONTINUATION	$755,788
2025	2021	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	1/24/2025	NON-COMPETING CONTINUATION	-$49,201
														Subtotal = $706,588

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	8/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $501,372 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	15	8/25/2021	NON-COMPETING CONTINUATION	$501,372
2021	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	13	3/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$385,298
2021	2019	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	3/8/2021	NON-COMPETING CONTINUATION	-$208,057
2021	2018	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	3/8/2021	NON-COMPETING CONTINUATION	-$177,241
														Subtotal = $501,372

Issue Date FY: 2020 ( Subtotal = $486,839 )
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	14	9/1/2020	NON-COMPETING CONTINUATION	$497,655
2020	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	13	8/31/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$40,069
2020	2019	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	6/19/2020	NON-COMPETING CONTINUATION	-$297,719
2020	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/20/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$246,834
														Subtotal = $486,839

Issue Date FY: 2019 ( Subtotal = $505,776 )
2019	2019	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/25/2019	NON-COMPETING CONTINUATION	$505,776
														Subtotal = $505,776

Issue Date FY: 2018 ( Subtotal = $505,776 )
2018	2018	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	8/16/2018	NON-COMPETING CONTINUATION	$505,776
2018	2017	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	8/16/2018	COMPETING CONTINUATION	$0
														Subtotal = $505,776

Issue Date FY: 2017 ( Subtotal = $519,200 )
2017	2017	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	9/21/2017	COMPETING CONTINUATION	$519,200
2017	2013	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	1/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $519,200

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/12/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $296,361 )
2013	2013	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/9/2013	NON-COMPETING CONTINUATION	$296,361
														Subtotal = $296,361

Issue Date FY: 2012 ( Subtotal = $307,110 )
2012	2012	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	9/4/2012	NON-COMPETING CONTINUATION	$307,110
														Subtotal = $307,110

Issue Date FY: 2011 ( Subtotal = $307,110 )
2011	2011	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	8/23/2011	NON-COMPETING CONTINUATION	$307,110
														Subtotal = $307,110

Issue Date FY: 2010 ( Subtotal = $372,708 )
2010	2010	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	9/20/2010	COMPETING CONTINUATION	$372,708
														Subtotal = $372,708

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	HENRY FORD HEALTH SYSTEM	2799 WEST GRAND BOULEVARD	DETROIT	MI	48202	WAYNE	USA	Kidney Diseases, Urology and Hematology Research	000	5	6/11/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $235,500 )
2008	2008	HENRY FORD HEALTH SYSTEM	2799 WEST GRAND BOULEVARD	DETROIT	MI	48202	WAYNE	USA	Kidney Diseases, Urology and Hematology Research	000	5	2/27/2008	NON-COMPETING CONTINUATION	$235,500
														Subtotal = $235,500

Issue Date FY: 2007 ( Subtotal = $240,307 )
2007	2007	CASE WESTERN RESERVE UNIV, HENRY FORD HLTH SCIENCES CTR	5600 NEW KING STREET, STE 200	TROY	MI	48098	OAKLAND	USA	Kidney Diseases, Urology and Hematology Research	000	4	3/1/2007	NON-COMPETING CONTINUATION	$240,307
														Subtotal = $240,307

Issue Date FY: 2006 ( Subtotal = $244,459 )
2006	2006	CASE WESTERN RESERVE UNIV, HENRY FORD HLTH SCIENCES CTR	5600 NEW KING STREET, STE 200	TROY	MI	48098	OAKLAND	USA	Kidney Diseases, Urology and Hematology Research	000	3	2/28/2006	NON-COMPETING CONTINUATION	$244,459
														Subtotal = $244,459

Issue Date FY: 2005 ( Subtotal = $247,632 )
2005	2005	CASE WESTERN RESERVE UNIV, HENRY FORD HLTH SCIENCES CTR	5600 NEW KING STREET, STE 200	TROY	MI	48098	OAKLAND	USA	Kidney Diseases, Urology and Hematology Research	000	2	2/28/2005	NON-COMPETING CONTINUATION	$247,632
														Subtotal = $247,632

Issue Date FY: 2004 ( Subtotal = $243,760 )
2004	2004	CASE WESTERN RESERVE UNIV, HENRY FORD HLTH SCIENCES CTR	5600 NEW KING STREET, STE 200	TROY	MI	48098	OAKLAND	USA	Kidney Diseases, Urology and Hematology Research	000	1	2/23/2004	NEW	$243,760
														Subtotal = $243,760

Grand Total All Awards = $6,426,858

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Novel Roles and Mechanisms of Proximal Tubule Mitochondrial Angiotensin II and Sirtuin 3 in Hypertension

Award Number: R01DK067299

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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