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Hypertension and glomerular injury in hyperhomocysteinemia - role of inflammatory exosomes

Award Number: R01DK054927
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Over the last five years, we have demonstrated that the activation of NOD-like receptor protein with pryin domain containing 3 (NLRP3) inflammasomes in podocytes triggers and promotes glomerular dysfunction and sclerosis during hyperhomocysteinemia (hHcy). Given that the NLRP3 inflammasomes are activated primarily in the cytosol, their products such as IL-1ß, IL-18 or high mobility group protein B1 (HMGB1) may not be secreted out of cells via a classical and Golgi apparatus-mediated delivery pathway. It is now imperative to address how NLRP3 activation-derived products are released out of podocytes to trigger the inflammatory response leading to injury in glomeruli. Our preliminary studies have shown that homocysteine (Hcy) stimulation or hHcy not only resulted in NLRP3 inflammasome activation within podocytes, but also increased the release of exosomes that are enriched with NLRP3 inflammasome products. Lysosomal acid sphingomyelinase (ASM) activation was importantly involved in hHcy-induced lysosome dysfunction, which reduced the degradation of multivesicular body (MVB) resulting in robust exosome secretion. We therefore hypothesize that an exosome secretory mechanism mediated by lysosomal ASM-ceramide signaling pathway is concurrently activated with NLRP3 inflammasomes in podocytes during hHcy and both work in concert to trigger or promote local inflammatory response, leading to glomerular injury and sclerosis. To test this hypothesis, three Specific Aims are proposed. Specific Aim 1 will determine whether lysosomal ASM-ceramide signaling pathway contributes to NLRP3 inflammasome activation and enhanced release of inflammatory exosomes in podocytes during hHcy, which together trigger local glomerular inflammation, injury and even sclerosis using Smpd1-/- mice, podocyte-specific Smpd1 transgenic mice (Smpd1trg/PodoCre), and their wild type littermates (WT/WT and Smpd1trg/Podowt). Specific Aim 2 will determine whether Hcy in vitro or hHcy in vivo stimulates the formation of MVBs containing NRLP3 inflammasome products in podocytes to release inflammatory exosomes and whether these inflamed exosomes induce glomerular dysfunction and injury. Specific Aim 3 will explore the molecular mechanisms by which lysosome trafficking and interactions with MVBs are altered upon Hcy stimulation to prolong the fate of MVBs, thereby promoting robust release of inflammatory exosomes in primary cultures of podocytes or glomeruli from Smpd1-/- and Smpd1trg/PodoCre mice and their wild type littermates. These proposed studies represent the first effort in the field to link the activation of NLRP3 inflammasomes in podocytes to the instigation of glomerular inflammatory response and injury. The findings may lead to a paradigm shift in how we understand the molecular mechanisms of glomerular inflammation during hHcy and in how to develop new therapeutic strategies to mechanistically counteract glomerular injury or end-stage renal disease during hHcy.


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 = $500,354 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	5/12/2023	NON-COMPETING CONTINUATION	$500,354
														Subtotal = $500,354

Issue Date FY: 2022 ( Subtotal = $500,354 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	5/19/2022	NON-COMPETING CONTINUATION	$500,354
														Subtotal = $500,354

Issue Date FY: 2021 ( Subtotal = $500,354 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	5/24/2021	NON-COMPETING CONTINUATION	$500,354
														Subtotal = $500,354

Issue Date FY: 2020 ( Subtotal = $500,354 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	21	6/11/2020	COMPETING CONTINUATION	$1
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	6/4/2020	COMPETING CONTINUATION	$500,354
2020	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	1/29/2020	NON-COMPETING CONTINUATION	-$1
														Subtotal = $500,354

Issue Date FY: 2017 ( Subtotal = $331,688 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	20	8/30/2017	NON-COMPETING CONTINUATION	$331,688
2017	2016	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	2/14/2017	EXTENSION WITH OR WITHOUT FUNDS	$37,084
2017	2015	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/14/2017	NON-COMPETING CONTINUATION	-$37,084
														Subtotal = $331,688

Issue Date FY: 2016 ( Subtotal = $331,688 )
2016	2016	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	7/18/2016	EXTENSION WITH OR WITHOUT FUNDS	$331,688
														Subtotal = $331,688

Issue Date FY: 2015 ( Subtotal = $331,688 )
2015	2015	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	7/28/2015	NON-COMPETING CONTINUATION	$331,688
														Subtotal = $331,688

Issue Date FY: 2014 ( Subtotal = $331,688 )
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	7/31/2014	NON-COMPETING CONTINUATION	$331,688
														Subtotal = $331,688

Issue Date FY: 2013 ( Subtotal = $331,688 )
2013	2013	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	8/13/2013	COMPETING CONTINUATION	$331,688
2013	2012	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	7/31/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $331,688

Issue Date FY: 2012 ( Subtotal = $311,365 )
2012	2012	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/15/2012	NON-COMPETING CONTINUATION	$311,365
														Subtotal = $311,365

Issue Date FY: 2011 ( Subtotal = $311,365 )
2011	2011	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/11/2011	NON-COMPETING CONTINUATION	$283,097
2011	2011	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	6/7/2011	NON-COMPETING CONTINUATION	$28,268
														Subtotal = $311,365

Issue Date FY: 2010 ( Subtotal = $314,511 )
2010	2010	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	3/18/2010	NON-COMPETING CONTINUATION	$314,511
														Subtotal = $314,511

Issue Date FY: 2009 ( Subtotal = $433,480 )
2009	2009	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Trans-NIH Recovery Act Research Support	001	12	7/13/2009	SUPPLEMENT FOR EXPANSION	$15,893
2009	2009	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/18/2009	NON-COMPETING CONTINUATION	$317,422
2009	2009	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Trans-NIH Recovery Act Research Support	002	12	8/31/2009	SUPPLEMENT FOR EXPANSION	$100,165
														Subtotal = $433,480

Issue Date FY: 2008 ( Subtotal = $316,625 )
2008	2008	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Kidney Diseases, Urology and Hematology Research	000	11	3/6/2008	COMPETING CONTINUATION	$316,625
														Subtotal = $316,625

Issue Date FY: 2006 ( Subtotal = $210,192 )
2006	2006	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Kidney Diseases, Urology and Hematology Research	000	10	3/29/2006	NON-COMPETING CONTINUATION	$210,192
														Subtotal = $210,192

Issue Date FY: 2005 ( Subtotal = $215,250 )
2005	2005	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Kidney Diseases, Urology and Hematology Research	000	9	5/2/2005	NON-COMPETING CONTINUATION	$215,250
														Subtotal = $215,250

Issue Date FY: 2004 ( Subtotal = $215,250 )
2004	2004	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	7	2/13/2004	NON-COMPETING CONTINUATION	$215,250
														Subtotal = $215,250

Issue Date FY: 2003 ( Subtotal = $215,250 )
2003	2003	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	6		COMPETING CONTINUATION	$215,250
														Subtotal = $215,250

Issue Date FY: 2002 ( Subtotal = $160,562 )
2002	2002	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	5	4/29/2002	NON-COMPETING CONTINUATION	$160,562
														Subtotal = $160,562

Issue Date FY: 2001 ( Subtotal = $165,051 )
2001	2001	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	4	5/11/2001	NON-COMPETING CONTINUATION	$165,051
														Subtotal = $165,051

Issue Date FY: 2000 ( Subtotal = $138,800 )
2000	2000	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	3	6/2/2000	NON-COMPETING CONTINUATION	$138,800
														Subtotal = $138,800

Grand Total All Awards = $6,950,686

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Hypertension and glomerular injury in hyperhomocysteinemia - role of inflammatory exosomes

Award Number: R01DK054927

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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