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Abstract: TH-PO777

Exosomes Play a Pivotal Role in Linking Proteinuria to Glomerulosclerosis by Mediating Podocyte-Mesangial Communication

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Liu, Zhao, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Liu, Xi, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Liu, Youhua, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
Background

Podocyte injury is the primary feature of the vast majority of glomerular diseases, while mesangial cell activation is the hallmark of glomerulosclerosis. How these two types of cells communicate in glomerular disease remains elusive. Exosomes act as membranous vesicle carriers and are involved in the pathogenesis of kidney disease by shuttling proteins and other materials between donor and recipient cells. Here, we tested whether exosomes play a role in mediating podocyte-mesangial communication in glomerular disease.

Methods

Exosomes secreted by injured podocytes were purified by differential centrifugation and characterized using nanoparticle tracking analysis and transmission electron microscopy. Differentially expressed proteins from podocyte-derived exosomes were analyzed by protein microarray, and sonic hedgehog (Shh) was identified as one of the most regulated proteins in the exosomes from injured podocytes. The potential role and mechanism by which exosomal-Shh mediates communication between podocytes and mesangial cells was investigated in vitro and in vivo.

Results

In vitro, we found an increased production of exosomes in mouse podocyte cells (MPC5) stimulated by angiotensin II (Ang II). Shh and activated N-Shh were encapsulated in exosomes isolated from Ang II-treated MPC5 cells (Ang II-Exo). The Ang II-Exo were able to induce the activation and proliferation of rat mesangial cells (RMC). In contrast, inhibition of exosome secretion with dimethyl amiloride, depletion of exosomes from conditioned medium or knockdown of Shh expression abolished the ability of Ang II-Exo to induce RMC activation. In vivo, the injection of podocyte-derived exosomes exacerbated glomerulosclerosis, which was negated by inhibitors of Shh signaling. Furthermore, blocking exosome secretion also ameliorated glomerulosclerosis following Ang II and adriamycin injury in mice.

Conclusion

Podocyte-derived exosomes play a critical role in mesangial cell activation and glomerulosclerosis by carrying Shh ligands. Therefore, strategies targeting exosomes may be a novel way to treat proteinuric kidney disease.