Endothelial dysfunction accelerates AKI-to-CKD transition by promoting β-catenin activation in macrophages

Nov 21, 2025American journal of physiology. Renal physiology

Blood vessel lining problems speed up kidney damage progression by activating a cell-signaling protein in immune cells

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Abstract

Endothelial dysfunction may contribute to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) by promoting profibrotic signaling.

Persistent fibrosis and sustained activation of β-catenin signaling were observed in a mouse model of severe ischemia-reperfusion injury, particularly in the absence of endothelial nitric oxide synthase (eNOS).
Impaired signaling involving nitric oxide, cyclic guanosine monophosphate, and protein kinase G exacerbated fibrosis by failing to inhibit β-catenin activity.
RNA sequencing post-injury showed an increase in genes associated with macrophage differentiation.
A biphasic macrophage response was identified, with M1-like macrophages predominating initially and shifting to M2-like macrophages, which persisted longer in eNOS knockout mice.
Inhibition of M2 macrophage polarization was linked to nitric oxide signaling, suggesting a connection between endothelial dysfunction and sustained M2 activation.
Depleting macrophages in eNOS-deficient mice decreased interstitial fibrosis and improved kidney function, indicating M2 macrophages' role in AKI-to-CKD progression.

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Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), resulting in long-term renal dysfunction. Although traditional risk factors such as hypertension, diabetes, and aging contribute to this transition, endothelial dysfunction has emerged as a central mediator. In a murine model of severe ischemia-reperfusion injury (IRI), we observed persistent fibrosis with sustained activation of β-catenin signaling, especially when there is an endothelial nitric oxide synthase (eNOS) deficiency. Impaired nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling exacerbated fibrosis by failing to suppress β-catenin activity. RNA sequencing atpost-IRI revealed upregulation of genes related to macrophage differentiation. Flow cytometry demonstrated a biphasic macrophage response: CD11bF4/80(M1-like) macrophages predominated on, shifting to CD11bF4/80(M2-like) macrophages by, and then resolving by. However, in eNOS knockout mice, M2 macrophages persisted beyond, indicating sustained fibrogenic signaling. In vitro, NO-cGMP-PKG signaling inhibited IL-4-induced M2 polarization via β-catenin degradation, linking endothelial dysfunction to prolonged M2 activation. In vivo, macrophage depletion in eNOS-deficient mice significantly reduced interstitial fibrosis and improved renal function, confirming an important pathogenic role of M2 macrophages in AKI-to-CKD progression. Furthermore, pharmacological enhancement of cGMP signaling using a phosphodiesterase-5 (PDE5) inhibitor frompost-IRI ameliorated fibrosis. Together, these findings suggest that endothelial dysfunction promotes a profibrotic macrophage milieu via Wnt/β-catenin activation and highlights the therapeutic potential of targeting NO-cGMP-β-catenin signaling to prevent CKD progression following AKI.Our study provides novel insights into the mechanisms underlying the transition from acute kidney injury (AKI) to chronic kidney disease (CKD), with a focus on the role of endothelial nitric oxide synthase (eNOS). We believe our findings, particularly their potential implications for developing new therapeutic strategies to prevent CKD progression, will be of significant interest to your readership and could significantly improve patient care. day 7day 1day 3day 7day 3day 7 + low + high NEW & NOTEWORTHY

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Endothelial dysfunction accelerates AKI-to-CKD transition by promoting β-catenin activation in macrophages

Abstract

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