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Myeloid Ferritin-CXCL3 Axis as a Driver of AKI-to-CKD Progression

Award Number: R01DK149168
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: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Myeloid Ferritin-CXCL3 Axis as a Driver of AKI-to-CKD Progression - Acute kidney injury (AKI) affects over 13 million people worldwide annually, with no effective therapies available to treat the condition or prevent its progression to chronic kidney disease. Following an acute kidney insult, recruited myeloid cells (specifically, macrophages and neutrophils) orchestrate immune responses that dictate whether kidneys undergo adaptive repair or progress to maladaptive disease. Leveraging the publicly available kidney precision medicine project and our rodent ScRNA sequencing data, we found that ferritin genes (ferritin heavy chain; FtH and ferritin light chain; FtL) are dominantly expressed by myeloid cells during AKI. Ferritin (Ft), an evolutionarily conserved protein that stores iron, exists as a spherical shell that is made up of FtH and FtL. To determine the significance of myeloid Ft in AKI, we generated novel transgenic mice with targeted deletion of both ferritin genes in the myeloid compartment (FtmKO). Using these mice, we discovered that while ferritin deletion does not affect acute injury severity following bilateral kidney ischemia reperfusion injury, it significantly improves long-term kidney function recovery and reduced maladaptive repair. Single-cell RNA sequencing of immune cells during the transition phase (7 days post-injury) revealed that wildtype kidneys accumulate a population of pro- inflammatory CCR2+ myeloid cells expressing high levels of CXCL3, a neutrophil chemoattractant, which was markedly lower in FtmKO mice. In vitro studies confirmed ferritin directly induces CXCL3 expression in macrophages. Additionally, wildtype kidneys also accumulated CCR2+ myeloid cells with heightened extracellular matrix regulatory signatures associated with fibrotic remodeling, which were diminished in mice without myeloid ferritin. At 28 days post-injury, wildtype mice exhibited sustained proximal tubular damage and significantly greater fibrosis compared to knockout mice. Based on these findings, we hypothesize that myeloid ferritin perpetuates inflammation via CXCL3 signaling, thereby sustaining proximal tubular injury and promoting maladaptive repair following AKI. We will test this hypothesis with two aims: (1) Determine whether targeted deletion of ferritin in CCR2+ cells after established AKI attenuates ongoing inflammation and maladaptive repair; (2) Evaluate whether inhibition of CXCL3-CXCR2 axis following AKI prevents disease progression and facilitates functional recovery. We will use genetic and pharmacological approaches in established AKI models, combined with integrated mechanistic studies to effectively test our hypothesis. This conceptually innovative proposal represents a paradigm shift from current AKI prevention approaches by determining the therapeutic potential of targeting myeloid ferritin (and its mediators) after established AKI, addressing a critical unmet clinical need for a condition that currently lacks treatment options and poses substantial global healthcare burden. Successful completion of this project will provide mechanistic insights into immune cell-mediated AKI-to-CKD progression while delivering a targeted AKI therapy that could transform clinical management of AKI survivors.


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 = $650,509 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/19/2026	NEW	$650,509
														Subtotal = $650,509

Grand Total All Awards = $650,509

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Myeloid Ferritin-CXCL3 Axis as a Driver of AKI-to-CKD Progression

Award Number: R01DK149168

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: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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