Small Extracellular Vesicles Mediate the Cross-Talk Between Hepatocytes and Renal Cells in Metabolic Dysfunction-Associated Steatohepatitis-Related Kidney Disease

Background: Metabolic dysfunction-associated steatohepatitis (MASH), which is defined as a multisystem disorder, is independently associated with the development of chronic kidney disease (CKD). Our previous study established a new mouse model resembles human MASH, demonstrating a causal relationship between MASH and CKD. Given the emerging role of extracellular vesicles (EVs) in mediating inter-organ communication, we investigated the contribution of EVs to MASH-associated kidney injury Methods: MASH was induced in C57BL/6J mice through a combination of western diet feeding and low-dose of CCl4 injections. Small EVs (sEVs) were isolated from liver tissue and serum by differential ultracentrifugation and characterized using transmission electron microscopy. To visualize hepatocyte-derived sEVs in vivo, Albumin-Cre; GFPf/f-CD63 (sEVs reporter) transgenic mice were used. Results: Mice with MASH exhibited pronounced glomerulosclerosis and tubular fibrosis. Circulating levels of sEVs were markedly elevated in MASH mice and correlated with the severity of both hepatic and renal injury. Hepatocyte-derived sEVs were increased dramatically in MASH mice compared to controls. Pharmacological inhibition of sEVs secretion with GW4869 led to improved renal function and a reduction in renal fibrosis of MASH mice. Utilizing hepatocyte-specific CD63-GFP reporter mice, we demonstrated that hepatocyte-derived sEVs are released into the circulation and taken up by LTL+ proximal tubular cells during MASH progression. Moreover, intravenous administration of serum-derived sEVs from MASH donor mice worsen renal function in healthy recipients. A similar exacerbation of kidney injury was observed following administration of hepatocyte-derived sEVs from MASH livers. In vitro, co-culture of primary mouse tubular epithelial cells (mTECs) with serum-sEVs from MASH mice induced a robust pro-inflammatory and injury-related phenotype. Conclusion: Hepatocyte-derived sEVs contribute to renal injury in MASH-associated CKD. These findings highlight a novel pathogenic liver-to-kidney communication axis mediated by sEVs and suggest that targeting sEVs may represent a promising therapeutic strategy for mitigating renal complications in MASH. Funding: NIDDK Support