Low‐Intensity Ultrasound‐Triggered Microbubble Cavitation Attenuates Diabetic Kidney Injury Partially by Reversing Endothelial Dysfunction

ABSTRACT Herein, we developed a novel non‐invasive therapeutic strategy, namely ultrasound‐triggered cavitation of diagnostic‐grade microbubbles (MBs), which delivers favorable rhythmic mechanical stimuli to reverse this core pathological defect of diabetic kidney disease (DKD). By systematically optimizing parameters between low‐intensity pulsed ultrasound (LIPUS) and the clinically approved diagnostic MB contrast agent Sonazoid, we established a standardized protocol (Sonazoid: 0.008 µg per injection; LIPUS: 3.4‐4.1 MHz, mechanical index 0.2; 10 min per session, twice weekly for 4 weeks) to precisely deliver localized favorable rhythmic mechanical stimuli to the renal microvasculature. In the db/db mouse model of progressive DKD, this therapeutic intervention significantly improved renal function, reduced albuminuria, and mitigated glomerular and tubular histological lesions. Ultrasound localization microscopy (ULM) verified a remarkable enhancement in renal cortical microcirculatory perfusion. Transcriptomic profiling of renal tissues revealed down‐regulation of key pathways involved in endothelial dysfunction, leukocyte chemotaxis, and fibrosis, accompanied by a shift toward an anti‐inflammatory and anti‐fibrotic phenotypic state. Our findings demonstrate that this therapeutic strategy generates favorable mechanical modulation at the microvascular level, effectively retarding DKD progression by restoring microvascular homeostasis and suppressing pathogenic inflammatory and fibrotic cascades. This approach offers a promising and translational platform technology for the management of microvascular diseases beyond DKD.