Piezo1 aggravates ischemia/reperfusion-induced acute kidney injury by Ca²⁺-dependent calpain/HIF-1α/Notch signaling

Macrophages play a vital role in the inflammation and repair processes of ischemia/reperfusion-induced acute kidney injury (IR-AKI). The mechanosensitive ion channel Piezo1 is significant in these inflammatory processes. However, the exact role of macrophage <i>Piezo1</i> in IR-AKI is unknown. The main purpose of this study was to determine the role of macrophage <i>Piezo1</i> in the injury and repair process in IR-AKI. Genetically modified mice with targeted knockout of <i>Piezo1</i> in myeloid cells were established, and acute kidney injury was induced by bilateral renal vascular clamping surgery. Additionally, hypoxia treatment was performed on bone marrow-derived macrophages <i>in vitro</i>. Our data indicate that Piezo1 is upregulated in renal macrophages in mice with IR-AKI. Myeloid <i>Piezo1</i> knockout provided protective effects in mice with IR-AKI. Mechanistically, the regulatory effects of Piezo1 on macrophages are at least partially linked to calpain signaling. Piezo1 activates Ca²⁺-dependent calpain signaling, which critically upregulates HIF-1α signaling. This key pathway subsequently influences the Notch and CCL2/CCR2 pathways, driving the polarization of M1 macrophages. In conclusion, our findings elucidate the biological functions of Piezo1 in renal macrophages, underscoring its role as a crucial mediator of acute kidney injury. Consequently, the genetic or pharmacological inhibition of Piezo1 presents a promising strategy for treating IR-AKI. Our data indicate that Piezo1 activates Ca²⁺-dependent calpain signaling, which critically upregulates HIF-1α signaling. This key pathway subsequently influences the Notch and CCL2/CCR2 pathways, driving the polarization of M1 macrophages. Notably, HIF-1α signaling plays a central role in regulating the inflammatory response, highlighting its importance in mediating macrophages activation and the progression of renal injury. Additionally, the production of pro-inflammatory factors and ROS, driven by HIF-1α, promotes apoptosis in renal tubular epithelial cells, further exacerbating renal damage.