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Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease

Award Number: R01DK112984
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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Project Summary/Abstract The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans have chronic kidney disease. Diabetes Mellitus is the leading risk factor for chronic kidney disease in the United States. Despite improved glycemic control, individuals with Diabetes Mellitus continue to develop and progress to diabetic kidney disease (DKD). In DKD, along with endothelial injury and mesangial expansion, podocyte loss directly contributes to the functional capacity to maintain the renal filtration barrier. Mitochondrial injury is also uniformly observed in DKD and is accompanied by mitochondrial DNA damage as well as altered expression of genes involved in mitochondrial biogenesis, function, and fragmentation. We recently reported the essential role for the zinc-finger transcription factor, Krüppel-like factor 6 (KLF6), in podocyte injury. Specifically, we demonstrated that KLF6 is an early inducible injury response gene that enhances mitochondrial respiratory complex IV (cytochrome c oxidase, COX) expression, thereby abrogating the release of cytochrome c and activation of apoptosis in the setting of cell stress. KLF6 maintains COX assembly by regulating the expression of key transcripts involved in mitochondrial replication, transcription, and function under cell stress. To date, this is the first study demonstrating a direct regulatory effect of a zinc-finger transcription factor on mitochondrial function in the podocyte. Our preliminary data also suggests that podocyte-specific loss of Klf6 (Klf6-/-) accelerated DKD in mice. In addition, we observed a significant increase in mitochondrial injury with podocyte loss in the diabetic Klf6-/- mice as compared to diabetic wildtype mice. Furthermore, we observed that modulating the level of KLF6 expression in the podocyte directly regulated mitochondrial structure, function, genes involved in COX assembly, and apoptosis. Finally, KLF6 expression was reduced in DKD as compared to healthy control subjects in three independent gene expression arrays from human kidney biopsies. The objective of this research proposal is to demonstrate that KLF6 is required to prevent mitochondrial dysfunction and podocyte injury in DKD. The long-term goal of our project is to identify “druggable” targets in restoring mitochondrial function in podocytes of diabetic kidney. This proposal will address a current gap in the field by demonstrating that COX assembly is critical to preventing mitochondrial dysfunction in podocytes of diabetic kidney. The potential impact of this proposed research is that it will shed new light on the critical role of respiratory complex assembly in improving mitochondrial function in the podocyte and slowing the rate of DKD progression in the kidney. Finally, deciphering the mechanism by which KLF6 regulates COX assembly will provide us with a novel pathway to target in DKD.


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: 2022 ( Subtotal = $349,000 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/10/2022	NON-COMPETING CONTINUATION	$349,000
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,000

Issue Date FY: 2021 ( Subtotal = $349,000 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/30/2021	NON-COMPETING CONTINUATION	$349,000
														Subtotal = $349,000

Issue Date FY: 2020 ( Subtotal = $349,000 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/27/2020	NON-COMPETING CONTINUATION	$349,000
														Subtotal = $349,000

Issue Date FY: 2019 ( Subtotal = $349,000 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/11/2019	NON-COMPETING CONTINUATION	$0
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/18/2019	NON-COMPETING CONTINUATION	$349,000
														Subtotal = $349,000

Issue Date FY: 2018 ( Subtotal = $348,857 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/25/2018	NON-COMPETING CONTINUATION	$348,857
														Subtotal = $348,857

Issue Date FY: 2017 ( Subtotal = $361,093 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/12/2017	NEW	$361,093
														Subtotal = $361,093

Grand Total All Awards = $2,105,950

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Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease

Award Number: R01DK112984

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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