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Renal Mechanism for Hypertension in Polycistic Kidney Disease

Award Number: K08DK106465
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Renal Mechanism for Hypertension in Polycistic Kidney Disease - ¿ DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a ciliopathic disorder that results in multiple kidney cysts and hypertension (HTN), which eventually leads to kidney failure. A hallmark of PKD is the early development of HTN, which is inadequately controlled by conventional therapies including angiotensin converting enzyme (ACE) inhibitors. In this regard, there is evidence for the activation of the intrarenal renin-angiotensin system (RAS) in PKD. In PKD only 2 to 3% of nephrons become cystic and the development of hypertension should be dependent upon inappropriate reabsorption of salt and water by non-cystic nephrons; the most likely site would be at the collecting duct. Indeed we have previously shown, in an immortalized collecting duct cell line from a cilia deficient PKD mouse model, increased expression of aquaporin (AQP2) and mislocalized apical vasopressin receptor (V2R) leading to increased transepithelial salt and water absorption compared to a control. Therefore, we hypothesize that increased salt and water reabsorption by the collecting duct, which leads to HTN in PKD, may be due to mislocalization/altered activity and regulation by intrarenal RAS of critical transport proteins. Thus the first Specific Aim (SA1) is to determine if there is increase salt and water transport in the collecting duct from Ift88 and Pkd1 conditional knockout mice compared to control. This will be accomplished by: assessing salt and water transport rates in isolated perfused tubules; measuring channel activity by patch clamp of micro-dissected split open collecting ducts; and testing expression and/or mislocalization of transport proteins utilizing in vivo biotinylation. In preliminary experiments we found that renal angiotensinogen (AGT) is up-regulated in both Ift88 and Pkd1 knockout mice and hypothesized that AGT may be an effective target for blockade of intrarenal RAS. Therefore, we recently tested a novel antisense oligonucleotide (ASO) targeting AGT and compared to conventional lisinopril therapy or no treatment in Pkd1 knockout mice and found that there was a significant reduction in the rate of renal cystic growth. AGT-ASO was not as effective as lisinopril in lowering blood pressure perhaps due to an AGT-ASO induced increase in renin levels. Therefore, (SA2) will determine the effect of inhibiting AGT or renin, or both, on hypertension and the rate of cystogenesis in Ift88 and Pkd1 models. This will be accomplished by determining whether AGT-ASO in combination with a renin inhibition (aliskiren) in Pkd1 and Ift88 conditional knockout mice leads to increased suppression of intrarenal renin, AGT, and angiotensin II levels, and whether this leads to better control of BP and a significant reduction in kidney cyst expansion compared to AGT-ASO treatment or lisinopril plus losartan. These proposed studies should lead to fundamentally new insights into the mechanism for PKD induced hypertension as well as test the therapeutic potential of a novel intrarenal RAS inhibitor for the treatment of HTN and renal cyst progression in PKD.


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: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $167,616 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/23/2019	NON-COMPETING CONTINUATION	$167,616
														Subtotal = $167,616

Issue Date FY: 2018 ( Subtotal = $167,616 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/28/2018	NON-COMPETING CONTINUATION	$167,616
														Subtotal = $167,616

Issue Date FY: 2017 ( Subtotal = $167,616 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	9/12/2017	NON-COMPETING CONTINUATION	$167,616
2017	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/21/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$21,167
2017	2015	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/21/2017	NEW	-$21,167
														Subtotal = $167,616

Issue Date FY: 2016 ( Subtotal = $154,138 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	9/12/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,138
2016	2015	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 Ashley Ave	CHARLESTON	SC	294258908	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/9/2016	NEW	$0
														Subtotal = $154,138

Issue Date FY: 2015 ( Subtotal = $159,233 )
2015	2015	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29403	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/27/2015	NEW	$159,233
														Subtotal = $159,233

Grand Total All Awards = $816,219

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Renal Mechanism for Hypertension in Polycistic Kidney Disease

Award Number: K08DK106465

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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