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Molecular Basis of Testican-2 Mediated Protection in CKD

Award Number: R01DK145514
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: 07/30/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Molecular Basis of Testican-2 Mediated Protection in CKD - ABSTRACT Podocyte injury plays a fundamental role in the initiation and progression of most etiologies of CKD. Studies to date have illuminated the critical importance of podocyte structure and podocyte interactions with the underlying GBM in maintaining kidney health. Testican-2 is a novel podocyte-derived protein that is secreted across the GBM and into circulation, with higher blood levels associated with reduced risk of CKD, CKD progression, and glomerulosclerosis. We find that testican-2 binds the extracellular matrix protein vitronectin and inhibits the interaction between vitronectin and integrin αVβ3, an important effector of podocyte injury. Further, testican-2 administration reduces integrin αVβ3 activation and podocyte injury in response to Adriamycin, in vitro and in vivo. By contrast, testican-2 deficient (Spock2-/-) mice have increased albuminuria and podocyte injury in response to Adriamycin, and this can be rescued with exogenous testican-2. Together, these findings identify testican-2 as a podocyte-derived mediator of kidney protection, opening an exciting potential therapeutic pathway in CKD. Aim 1 will establish the protective effect of circulating testican-2 in clinically relevant kidney disease models. Aim 1A will test the hypothesis that podocyte-specific testican-2 deficiency increases kidney damage severity in murine models of FSGS (APOL1 transgenic mice) and DKD (streptozotocin), with assessment of kidney function (proteinuria, creatinine, GFR), histopathology, electron microscopy, and other markers of glomerular injury. In addition, we will use podocyte-specific integrin β3 null mice to show that kidney damage due to testican-2 deficiency requires integrin αVβ3 activation. Aim 1B will test the hypothesis that increasing circulating testican-2 levels can attenuate and rescue kidney damage in both Spock2-/- mice and WT littermates, using the same read-outs outlined in Aim 1A; interaction between this exogenous testican-2 and vitronectin in the kidney will be confirmed, with the mechanism of testican-2 mediated protection further characterized in glomerular fractions of kidney lysates. Aim 2 will determine the structural basis of testican-2 mediated podocyte protection. Aim 2A will determine the first structure of testican- 2 in complex with vitronectin, expanding 3D structural studies performed to date by negative staining to atomic resolution using CryoEM, with the goal to map the contact residues at the testican-2/vitronectin interface. Aim 2B will test the hypothesis that disruption of the testican-2/vitronectin interface abrogates testican-2 mediated podocyte protection. Key testican-2 residues at this interface will be modified by site-directed mutagenesis and binding affinities for WT and mutant testican-2(s) with vitronectin will be assessed. Structure-activity studies for WT and mutant testican-2(s) will be conducted using cultured podocytes exposed to Adriamycin, with assessment of actin cytoskeleton disruption, cell motility and viability, and αVβ3 activation and signaling (including phosphoproteomic analysis). If successful, these studies will establish a new mechanism of podocyte protection relevant to common CKD etiologies, poised for structure-informed drug development.


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: 2027 ( Subtotal = $0 )
2027	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/23/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $561,565 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/30/2026	NEW	$561,565
														Subtotal = $561,565

Grand Total All Awards = $561,565

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Molecular Basis of Testican-2 Mediated Protection in CKD

Award Number: R01DK145514

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: 07/30/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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