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Podocyte-Proximal Tubule Interactions 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)
PERIOD OF PERFORMANCE START DATE: 06/12/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Podocyte-Proximal Tubule Interactions in Diabetic Kidney Disease - While glycemic control, RAAS blockade, and SGLT2i are important therapies, a significant proportion of these individuals with diabetic kidney disease (DKD) still progress to end-stage kidney disease. Along with endothelial injury and mesangial expansion, podocyte loss compromises the glomerular filtration barrier, leading to initial kidney injury in DKD. Although podocyte loss is the inciting event, recent studies suggest that the severity of proximal tubule (PT) injury is the primary determinant of DKD progression. In this proposal, the hypothesis is that the signaling between podocytes and PT cells is critical to preventing the progression of DKD. To ascertain how podocytes regulate PT health in DKD, mice with podocyte-specific expression of human Krüppel-Like Factor 6 (KLF6), a zinc finger transcription factor critical for podocyte homeostasis, was generated. These mice exhibited significantly less podocyte loss, glomerulosclerosis, PT injury, and interstitial fibrosis than the control mice under diabetic conditions. While it was initially suspected this improvement in PT injury was due to a reduction in podocyte loss, single nuclei RNA-sequencing demonstrated that podocyte KLF6 primes Ca2+/calmodulin-dependent protein kinase ID (CaMK1D) signaling in the first segment of the PT, proximal to the podocytes. The podocyte secretome from the KLF6 mice mitigated mitochondrial injury in PT cells under high glucose conditions, but the genetic and pharmacological inhibition of Camk1d in PT cells negated these protective effects by exacerbating mitochondrial injury and reducing cell survival. Utilizing a combination of tandem mass spectrometry from the podocyte secretome and single nuclei ATAC-sequencing, it was observed that KLF6 triggers the release of the N-glycosylated apolipoprotein J (ApoJ) from podocytes by inducing the expression of genes critical to N-glycosylation. Interestingly, previous studies report increased glomerular ApoJ expression and urinary ApoJ levels in individuals with early DKD. ApoJ also binds to low- density lipoprotein-related protein 2 (LRP2) and undergoes cellular uptake in PT cells. Subsequently, ApoJ binds to calmodulin to activate CaMKK-CaMK1D signaling to attenuate mitochondrial injury under diabetic conditions. Based on these data, the hypothesis is that the podocyte preconditions the PT against injury through ApoJ-CaMK1D signaling to mitigate the progression of DKD. This hypothesis will be tested through the following specific aims: (1) Determine the salutary role of N-glycosylated ApoJ signaling in DKD, (2) Ascertain how ApoJ primes CaMK1D signaling in PT cells in DKD, and (3) Establish how the activation of CaMK1D signaling preconditions the PT cells against injury in DKD. This proposal will address a current gap in the field by elucidating novel mechanism(s) by which the podocyte regulates PT health in DKD. The long-term goal of our project is to identify the mechanism(s) that mitigate PT injury in DKD so it can be leveraged as a therapeutic strategy for individuals with rapidly progressing 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: 2025 ( Subtotal = $688,303 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/13/2025	COMPETING CONTINUATION	$688,303
														Subtotal = $688,303

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

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	001	6	7/15/2022	NON-COMPETING CONTINUATION	$0
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
														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	000	3	4/18/2019	NON-COMPETING CONTINUATION	$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
														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 = $2,794,253

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Podocyte-Proximal Tubule Interactions 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)

PERIOD OF PERFORMANCE START DATE: 06/12/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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