Exosome Biogenesis and Lysosome Function Determine Podocyte Exosome Release and Glomerular Inflammatory Response during Hyperhomocysteinemia.

Autor:	Huang D; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Li G; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Bhat OM; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Zou Y; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Li N; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Ritter JK; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia., Li PL; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia. Electronic address: pin-lan.li@vcuhealth.org.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2022 Jan; Vol. 192 (1), pp. 43-55. Date of Electronic Publication: 2021 Oct 27.
DOI:	10.1016/j.ajpath.2021.10.005
Abstrakt:	Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation in podocytes is reportedly associated with enhanced release of exosomes containing NLRP3 inflammasome products from these cells during hyperhomocysteinemia (hHcy). This study examined the possible role of increased exosome secretion during podocyte NLRP3 inflammasome activation in the glomerular inflammatory response. Whether exosome biogenesis and lysosome function are involved in the regulation of exosome release from podocytes during hHcy in mice and upon stimulation of homocysteine (Hcy) in podocytes was tested. By nanoparticle tracking analysis, treatments of mice with amitriptyline (acid sphingomyelinase inhibitor), GW4869 (exosome biogenesis inhibitor), and rapamycin (lysosome function enhancer) were found to inhibit elevated urinary exosomes during hHcy. By examining NLRP3 inflammasome activation in glomeruli during hHcy, amitriptyline (but not GW4869 and rapamycin) was shown to have an inhibitory effect. However, all treatments attenuated glomerular inflammation and injury during hHcy. In cell studies, Hcy treatment stimulated exosome release from podocytes, which was prevented by amitriptyline, GW4869, and rapamycin. Structured illumination microscopy revealed that Hcy inhibited lysosome-multivesicular body interactions in podocytes, which was prevented by amitriptyline or rapamycin but not GW4869. Thus, the data from this study shows that activation of exosome biogenesis and dysregulated lysosome function are critically implicated in the enhancement of exosome release from podocytes leading to glomerular inflammation and injury during hHcy. (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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