"Pulsed Ultrasound Targeted to the Spleen Mitigates Against Kidney Injury and Promotes Kidney Repair" 6 views

Acute kidney injury (AKI) is a condition characterized by a sudden decline in kidney function. Episodes of AKI may predispose patients to progression to chronic kidney disease (CKD). AKI represents a clinical syndrome with diverse etiologies rather than a single disease entity. In this thesis, I took multiple approaches to understand the pathophysiology of AKI and CKD that serve as foundations for new therapeutic options. Splenic Pulsed Ultrasound for the Prevention of AKI/CKD. Research from the Okusa lab has previously shown that pulsed ultrasound (pUS) can attenuate the extent of kidney ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway, a neural circuit that regulates the body’s immune response to pathogens and tissue injury. The efficacy of pUS in AKI of other etiologies and its long-term impact has not been determined. For the current study, a new ultrasound system with an optimized regimen was constructed and designed to specifically target the mouse spleen. pUS was delivered to mice 24 hours prior to toxin-induced AKI (folic acid), sepsis associated AKI (lipopolysaccharide) or ischemic AKI (bilateral kidney IRI). Mice were monitored and assessed for markers of kidney function, kidney fibrosis and inflammation. Compared to sham-treated mice, mice that received spleen-targeted pUS had reduced AKI after folic acid, lipopolysaccharide, or bIRI. pUS-treated mice displayed a reduction in the increase in myeloid cell infiltration to the kidneys after folic acid and bIRI. pUS-treated mice displayed reduced fibrosis 14 days after folic acid. These data demonstrate that ultrasound targeted to the spleen is a safe and effective therapy for the prevention of AKI of multiple etiologies and the progression to CKD. These findings will be used to advance the human translation of ultrasound as a preventative measure for patients with AKI and CKD. Mechanosensitive ion channels in AKI/CKD. Mechanosensitive ion channels (MSCs) are membrane proteins that play a significant role in mediating the transduction of mechanical stimuli into electrochemical signals. Studies have shown that certain MSCs, including Piezo1, are activated by ultrasound stimulation. Furthermore, MSCs have been shown to play a role in the pathogenesis of kidney diseases. Thus, our initial effort was to better understand the role of Piezo1 in kidney disease pathogenesis. Here, we demonstrated that Piezo1 expression is increased in the kidneys after AKI. We generated mice deficient in hematopoietic cell Piezo1 and found that hematopoietic deficiency of Piezo1 worsened AKI and CKD in both males and females. Injection of GsMTx4, a broad pharmacological inhibitor of both PIEZO and TRP channels, however, reduced AKI and CKD. These studies uncovered a complex and potentially cell specific role of MSCs in the pathogenesis of kidney disease. Future studies will focus on elucidating the cell specific role of Piezo1 and additional MSCs in kidney diseases. Perivascular cell Dynamin-related protein 1 and AKI/CKD. In a separate project, I explored the role of the mitochondrial fission gene, Dynamin-related protein 1 (Drp1), in kidney perivascular cells (PVCs). PVCs have an important role in the AKI to CKD transition. We previously demonstrated that proximal tubule deletion of Drp1 attenuated kidney injury and fibrosis after IRI. To understand the role of Drp1 and mitochondrial dynamic dysfunction in kidney PVCs, primary kidney PVCs and multiple male and female mouse models of AKI and CKD were used. PVC specific germline Drp1 heterozygous and homozygous male and female mice were generated. Primary kidney PVCs displayed increased mitochondrial fission after in vitro and ex vivo injury. Both germline and inducible partial reductions of PVC Drp1 in mice provided protection against kidney injury. Intriguingly, however, while homozygous deficiency of Drp1 was protective when Drp1 deletion occurred immediately prior to injury, a homozygous germline deficiency of Drp1 exacerbated kidney injury. The role of Drp1 in kidney PVCs was similar between males and females despite established mitochondrial sex differences. This study uncovered the complex role of Drp1 in kidney PVCs and suggests an importance of both the timing and degree of Drp1 deficiency in mediating protection from AKI and CKD. Although each study employed a distinct approach, collectively they advance our understanding of AKI and CKD and highlight promising avenues for the development of new therapeutic strategies.

PHD (Doctor of Philosophy)

Acute Kidney Injury; Therapeutic Ultrasound; Chronic Kidney Disease; Mitochondrial Dynamics ; Dynamin Related Protein 1 ; Perivascular Cell; Mechanosensative Ion Channels; Piezo 1

English

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2025-11-30