HIF-1α/A2BAR signalling pathway alleviates kidney fibrosis after ischemia–reperfusion injury by preventing macrophage-to-myofibroblast transition

Abstract

The activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic or ischemic conditions plays a crucial in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). Inflammatory macrophages are potentially involved in kidney fibrosis, and the macrophage-to-myofibroblast transition (MMT) is a significant contributor to renal fibrosis. This study investigates the role of HIF-1α in modulating MMT during renal fibrosis development post-ischemia–reperfusion injury (IRI). Using a model of AKI-to-CKD transition in wild-type (WT) and HIF-1α- knockdown mice, we evaluated kidney fibrosis, macrophage infiltration, and MMT. The influence of the HIF-1α/A2BAR signalling pathway on MMT was assessed by modulating adenosine A2B receptor (A2BAR) activity. In WT mice, IRI-induced renal fibrosis was associated with increased macrophage infiltration and MMT marker co-expression (F4/80⁺–α-SMA⁺), alongside activation of the HIF-1α and A2BAR pathways. Following HIF-1α knockdown, macrophage infiltration and MMT increased significantly, accompanied by a marked aggravation of renal fibrosis. Inhibition of A2BAR signalling with the antagonist MRS1754 in HIF-1α-knockdown mice further increased macrophage infiltration and MMT, aggravating renal fibrosis post-IRI. In contrast, activation of A2BAR signalling with the agonist BAY60-6583 markedly decreased macrophage infiltration and MMT, effectively mitigating renal fibrosis. This study underscores the critical role of MMT in renal fibrosis after IRI and suggests that the HIF-1α/A2BAR signalling pathway mitigates fibrosis by modulating macrophage infiltration and MMT, providing new insights into the mechanisms underlying the AKI-to-CKD progression.