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Mechanisms of subclinical renal injury in females following AKI: implications for adverse pregnancy outcomes

Award Number: R01DK134695
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: 02/08/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of subclinical renal injury in females following AKI: implications for adverse pregnancy outcomes - Recent large-scale clinical studies report that women with a history of acute kidney injury (AKI) have abnormally high rates of adverse maternal and fetal outcomes during pregnancy, despite clinical evidence of renal recovery prior to conception as defined by measurement of serum creatinine. We established a pregnancy post-AKI model in Sprague Dawley rats using ischemia reperfusion (IR) as an experimental model of AKI which recapitulates many of the clinical findings, including fetal growth restriction. The goal of this proposal is to address a critical gap in knowledge regarding the mechanisms by which AKI predisposes females to adverse outcomes in pregnancy. Our central hypothesis is that AKI prior to conception impairs the renal, hemodynamic and immune adaptations required for a healthy pregnancy by decreasing nitric oxide (NO) bioavailability. Normal pregnancy is characterized by profound adaptations in almost every organ system to meet the demands of the fetus while maintaining the physiological needs of the mother. NO is a central mediator of the renal and cardiovascular adaptations in healthy pregnancy, and decreases in NO bioavailability lead to adverse maternal and fetal outcomes, including low birth weight. We have also shown that NO synthase (NOS) is required for females to increase T regulatory cells (Tregs), and failure to expand Tregs in pregnancy induces renal and vascular dysfunction in the mother and promotes fetal growth restriction. There is growing evidence that the renal NOS system is impaired following AKI in males. The impact of AKI on NO/NOS in females is unknown. The impact of AKI on physiological adaptations to pregnancy, including increases in NO bioavailability are unknown. Our hypothesis is supported by strong preliminary data showing AKI prior to pregnancy 1) decreases renal NOS expression prior to conception and in pregnancy, 2) results in subclinical injury prior to pregnancy and renal injury in pregnancy, 3) impairs plasma volume expansion, 4) impairs vascular function in pregnancy, and 5) decreases Treg expansion in pregnancy. Aim 1 will test the hypothesis that AKI induces reductions in NO bioavailability that are exacerbated in pregnancy resulting in renal and vascular dysfunction. We propose that AKI results in the failure to appropriately increase NO-mediated hemodynamic adaptations and loss of NO-mediated plasma volume expansion leading to poor maternal and fetal outcomes in pregnancy. Aim 2 will test the hypothesis that failure to upregulate Tregs in pregnancy contributes to adverse pregnancy outcomes post-AKI. We will determine how AKI prior to pregnancy impacts Tregs and if increasing Tregs during pregnancy improves fetal growth and maternal outcomes. We propose that AKI results in the failure to increase NO which is required for Treg expansion, contributing to further decreases in NO. Results will provide a critically needed pre-clinical foundation to elucidate the mechanisms underlying poor pregnancy outcomes after AKI, give evidence for improved pre- and perinatal care guidelines, and potentially identify novel therapeutic targets for clinical trials.


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: 2026 ( Subtotal = $452,213 )
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/30/2026	NON-COMPETING CONTINUATION	$452,213
														Subtotal = $452,213

Issue Date FY: 2025 ( Subtotal = $406,991 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/4/2025	NON-COMPETING CONTINUATION	$406,991
														Subtotal = $406,991

Issue Date FY: 2024 ( Subtotal = $434,124 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/17/2024	NON-COMPETING CONTINUATION	$27,132
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/6/2024	NON-COMPETING CONTINUATION	$406,992
														Subtotal = $434,124

Issue Date FY: 2023 ( Subtotal = $465,713 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/6/2023	NEW	$465,713
														Subtotal = $465,713

Grand Total All Awards = $1,759,041

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Mechanisms of subclinical renal injury in females following AKI: implications for adverse pregnancy outcomes

Award Number: R01DK134695

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: 02/08/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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