Guangbi (George) Li, Ph.D.
Department: Department of Pharmacology and Toxicology
Molecular Medicine Research Building, Room 3048
1220 East Broad Street
Wuchang University of Technology, B.A., 2013
- Virginia Commonwealth University, Ph.D., 2017
Molecular mechanisms of podocyte dysfunction and injury. Our recent studies have shown that lysosome-dependent autophagic flux is crucial for the maintenance of podocyte differentiation and function. Lysosome dysfunction resulting in autophagic deficiency can lead to podocyte dedifferentiation and chronic renal degenerative diseases. Recent studies in our laboratory have provided the first experimental evidence indicating that hyperhomocysteinemia (hHcy) not only serves as a risk factor for end-stage renal disease, but also as an important pathogenic factor directly resulting in glomerular injury and consequent sclerosis. Anandamide has anti-inflammatory properties that protect podocytes from Hcy-induced injury, while resolvin D1 and 17S-hydroxy DHA have a beneficial effect on podocyte injury and glomerular sclerosis by inhibiting NLRP3 inflammasome activation. Additionally, adiponectin inhibits pannexin-1 channel activity in podocytes through the activation of acid ceramidase and associated elevation of intracellular S1P.
Regulation of exosome secretion by TRPML1 channel in podocytes. Exosome release from podocytes is increasingly being recognized as not only a biomarker, but also a pathogenic factor in glomerular diseases. Our recent studies have shown that the TRPML1 channel plays a crucial role in regulating lysosome trafficking and exosome release from podocytes, and that acid ceramidase is essential for its normal function. In addition, exosome secretion has been found to be activated concurrently with NLRP3 inflammasomes in podocytes during Hcy stimulation. The release of NLRP3 inflammasome products may be mediated by exosomes, and reactive oxygen species has been shown to contribute to inflammatory exosome secretion from podocytes by inhibiting TRPML1 channel activity. These findings suggest that targeting inflammatory exosome release could be a novel approach to preventing podocyte injury and glomerular sclerosis during hHcy.
Acid ceramidase as a novel therapeutic target for treatment of podocytopathy and nephrotic syndrome. Normal function of lysosomes as the major degradative compartments to renew cellular activity is essential for maintenance of podocyte structural and functional integrity. In our recent studies, we have found that podocyte-specific knockout of Asah1 gene induces podocytopathy and associated nephrotic syndrome (NS) in mice. We have also demonstrated acid ceramidase (AC) is critical for TRPML1 channel-mediated Ca2+ release, which controls lysosome-MVB interaction and exosome release in podocytes. Asah1 gene defect inhibits TRPML1 channel activity and thereby enhances exosome release, which may contribute to the development of podocytopathy and associated NS. It is anticipated that our findings may identify lysosomal acid ceramidase as a novel therapeutic target for prevention or treatment of podocytopathy.
- Li G, Li CX, Xia M, Ritter JK, Gehr TWB, Boini KM, Li PL. Enhanced epithelial-to-mesenchymal transition associated with lysosome dysfunction in podocytes: role of p62/Sequestosome 1 as a signaling hub. Cell Physiol Biochem. 35(5):1773-86, 2015. PMCID: PMC4391077
- Li G, Xia M, Abais JM, Boini K, Li PL, Ritter JK. Protective action of anandamide and its COX-2 metabolite against homocysteine-induced NLRP3 inflammasome activation and injury in podocytes. J Pharmacol Exp Ther. 358(1):61-70, 2016. PMCID: PMC4931881
- Li G, Chen Z, Zhang Q, Abais JM, Conley SM, Gehr TWB, Ritter JK, Li PL. NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. J Lipid Res. 58(6):1080-1090, 2017. PMCID: PMC5454504
- Li G, Zhang Q, Hong J, Ritter JK, Li PL. Inhibition of pannexin-1 channel activity by adiponectin in podocytes: Role of acid ceramidase activation. Biochim Biophys Acta Mol Cell Biol Lipids. 1863(10):1246-1256, 2018. PMCID: PMC6180945
- Li G, Huang D, Hong J, Bhat OM, Yuan X, Li PL. Control of Lysosomal TRPML1 Channel Activity and Exosome Release by Acid Ceramidase in Mouse Podocytes. Am J Physiol Cell Physiol. 317(3):C481-C491, 2019. PMCID: PMC6766620
- Li G, Kidd J, Kaspar C, Dempsey S, Bhat OM, Camus S, Ritter JK, Gehr TWB, Gulbins E, Li PL. Podocytopathy and Nephrotic Syndrome in Mice with Podocyte-Specific Deletion of the Asah1 Gene: Role of Ceramide Accumulation in Glomeruli. Am J Pathol. 190(6):1211-1223, 2020. PMCID: PMC7280759
- Li G, Huang D, Li N, Ritter JK, Li PL. Regulation of TRPML1 Channel Activity and Inflammatory Exosome Release by Endogenously Produced Reactive Oxygen Species in Mouse Podocytes. Redox Biol. 43:102013, 2021. PMCID: PMC8163985
- Li G, Huang D, Zou Y, Kidd J, Gehr TWB, Li N, Ritter JK, Li PL. Impaired autophagic flux and dedifferentiation in podocytes lacking Asah1 gene: Role of lysosomal TRPML1 channel. Biochim Biophys Acta Mol Cell Res. 1870(1):119386, 2022. PMCID: PMC9869931