[R01] Myeloid Ferritin-CXCL3 Axis as a Driver of AKI-to-CKD Progression

Ente: National Institute of Diabetes and Digestive and Kidney Diseases

Scadenza: 2031-04-30

Importo max: 650.509 EUR

Paese: US

Descrizione

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 Istituzione: UNIVERSITY OF ALABAMA AT BIRMINGHAM PI: Subhashini Bolisetty Progetto: 1R01DK149168-01

Settori: National Institute of Diabetes and Digestive and Kidney Diseases

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.