Mechanosensitive Ca2+ channel TRPV1 activated by low‐intensity pulsed ultrasound ameliorates acute kidney injury through Notch1‐Akt‐eNOS signaling

Abstract Acute Kidney Injury (AKI) is a significant medical condition characterized by the abrupt decline in kidney function.Low‐intensity pulsed ultrasound (LIPUS), a non‐invasive therapeutic technique employing low‐intensity acoustic wave pulses, has shown promise in promoting tissue repair and regeneration. A novel LIPUS system was developed and evaluated in rat AKI models, focusing on its effects on glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine (SCr), and the Notch1‐Akt‐eNOS signaling pathway. The results demonstrated that LIPUS treatment improved GFR, BUN, SCr levels, and renal pathology in AKI rats. In vitro experiments using HUVEC cells revealed that LIPUS stimulation promoted angiogenesis, cell migration mechanically‐dependent calcium ion influx, which was partially attenuated by TRPV1 knockdown. RNA sequencing analysis indicated LIPUS‐induced activation of the Notch pathway, phosphorylation of Akt and eNOS. Furthermore, inhibition or genetic silencing of Notch1 abolished the beneficial effects of LIPUS on angiogenesis, renal function, and Akt‐eNOS phosphorylation in both cells and AKI rats. These findings suggest that LIPUS‐induced calcium influx promotes Akt‐eNOS phosphorylation, nitric oxide (NO) production, angiogenesis, and improved renal function in AKI via Notch1‐Akt‐eNOS signaling, positioning LIPUS as a promising therapeutic strategy for AKI by targeting vascular regeneration.