Guangbi (George) Li, Ph.D.

Assistant Professor

Guangbi (George) Li, Ph.D.

Department: Department of Pharmacology and Toxicology

Email: guangbi.li@vcuhealth.org

Address/Location:
Molecular Medicine Research Building, Room 3048
1220 East Broad Street
Box 980613
Richmond, Virginia

Education

  • Wuchang University of Technology, B.A., 2013

  • Virginia Commonwealth University, Ph.D., 2017

Research interests:

  • Exosome-mediated intercellular communication in glomerular disease.
  • Renal medullary regulation of blood pressure by telocyte-derived exosomes.
  • Podocyte Piezo1 channel in mechanosensing of glomerular hyperfiltration.
  • Ceramide metabolism in podocytopathy and nephrotic syndrome.
  • TRPML1 channel in lysosomal regulation of exosome release.

Regulation of exosome release by TRPML1 channel in podocytes. There is increasing evidence that increased exosome release from podocytes may not only be a biomarker of glomerular diseases, but also a pathogenic factor in these diseases through its cell-to-cell communication function. However, the mechanisms by which exosome secretion from podocytes is regulated remain unknown. Recently, I have demonstrated that TRPML1 channel regulates lysosome trafficking and thereby controls lysosome- multivesicular body (MVB) interaction and exosome release in podocytes. The normal function of acid ceramidase (AC) is essential for Ca2+ release through TRPML1 channel. The activation of TRPML1 channel by sphingosine, an AC product, contributes to lysosome trafficking and fusion to MVBs, which may result in MVB degradation and reduction of exosome release from podocytes. Moreover, I have shown that endogenously produced reactive oxygen species amplifies exosome secretion from podocytes through inhibition of TRPML1 channel activity. Our findings suggest that TPRML1 channel regulates exosome release by controlling lysosome trafficking and lysosome-dependent MVB degradation in podocytes.

Contribution of podocyte-derived exosomes to inflammatory glomerular disease. NLRP3 inflammasome has been implicated in podocyte injury and glomerular sclerosis in response to hyperhomocysteinemia (hHcy) and obesity. However, it remains unknown how the products of NLRP3 inflammasome in cytoplasm are secreted out of podocytes. In my recent studies, I have shown that an exosome secretory mechanism is concurrently activated with NLRP3 inflammasomes in podocytes during hHcy and obesity. The release of NLRP3 inflammasome products such as IL-1β and IL-18 from podocytes may be mediated by exosomes. Mechanistic studies revealed that acid sphingomyelinase plays a key role in this process by regulating lysosome–MVB interaction, which can determine MVB degradation and exosome release in podocytes. Our findings provide the first evidence that targeting exosome release may be a novel therapeutic strategy to prevent the development of podocyte injury and glomerular sclerosis under pathological conditions such as hHcy and obesity.

Acid ceramidase in 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. However, it remains poorly understood whether lysosomal proteins participate in the regulation of podocyte function. In my recent studies, I have found that podocyte-specific knockout of Asah1 gene induces podocytopathy and associated nephrotic syndrome (NS) in mice. I 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. Moreover, it has been found that the inhibition of TRPML1 channel activity due to Asah1 gene deletion impairs autophagic flux in podocytes, leading to autophagosome accumulation and dedifferentiation. These pathological mechanisms may contribute to the development of podocytopathy and associated NS. It is anticipated that my findings may identify lysosomal AC as a novel therapeutic target for prevention or treatment of MCD-related podocytopathy.

Molecular mechanisms of podocyte dysfunction and injury. My research has established a new concept that lysosome-dependent autophagic flux is essential for maintenance of differentiation and normal function of podocytes. The autophagic deficiency due to lysosome dysfunction may induce podocyte dedifferentiation, leading to podocyte dysfunction and chronic renal degenerative diseases such as glomerular sclerosis. Recent studies in our laboratory have provided the first experimental evidence indicating that 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. Based on my findings, it was concluded that anandamide has anti-inflammatory properties, protecting podocytes from Hcy-induced injury by inhibition of NLRP3 inflammasome activation through its cyclooxygenase-2 metabolite, prostaglandin E2-ethanolamide. Moreover, I found that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of resolvin D1 and 17S-hydroxy DHA on Hcy-induced podocyte injury and glomerular sclerosis. The pannexin-1 channel has been reported to mediate the release of ATP that is involved in local tissue inflammation, obesity, and many chronic degenerative diseases. Recently, I have demonstrated that adiponectin inhibits pannexin-1 channel activity in podocytes through activation of acid ceramidase and associated elevation of intracellular S1P.
Anti-inflammatory and antihypertensive actions of AEA-COX-2 signaling pathway. Anandamide (AEA) is the N-acyl ethanolamide of arachidonic acid, an agonist of cannabinoid and non-cannabinoid receptors in the body. The kidneys are enriched in AEA and in enzymes that metabolize AEA, but the roles of AEA and its metabolites in the kidney remain poorly understood. Recently, I have demonstrated that exogenous AEA can attenuate the progression of podocyte injury, glomerular inflammation, and glomerulosclerosis in mice with hHdy via inhibition of NLRP3 inflammasome activation in podocytes. The anti-inflammatory actions of AEA depend on prostaglandin E2-ethanolamide (PGE2-EA), the COX-2 product of AEA. Moreover, I have reported that intramedullary inhibition of AEA hydrolysis by isopropyl dodecyl fluorophosphate (IDFP) results in the elevation of endogenous AEA in renal medulla and thereby induces diuresis and natriuresis in mice. Also, the diuretic actions of endogenous AEA are attributed to COX-2-dependent metabolism of AEA and production of PGE2-EA. These studies have uncovered novel roles and mechanisms of AEA in kidney health and disease.

Selected publications:

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. Li G, Huang D, Bhat OM, Poklis JL, Zhang A, Zou Y, Kidd J, Gehr TWB, Li PL. Abnormal Podocyte TRPML1 Channel Activity and Exosome Release in Mice with Podocyte-Specific Asah1 Gene Deletion. Biochim Biophys Acta Mol Cell Biol Lipids. 1866(2):158856, 2021. PMCID: PMC7770122
  7. 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
  8. Huang D, Kidd J, Zou Y, Wu X, Gehr TWB, Li PL, Li G. Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity. Inflammation. 46(5):2037-2054, 2023. PMCID: PMC10777441
  9. Huang D, Kidd J, Zou Y, Wu X, Li N, Gehr TWB, Li PL, Li G. Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation. Am J Physiol Renal Physiol. 326(6):F988-F1003, 2024. PMCID: PMC11380990
  10. Li G, Huang D, Kidd JM, Zou Y, Wu X, Zhang Y, Gehr TWB, Li N, Li PL. Acid Ceramidase as a Novel Target for Adiponectin Receptor Agonist to Abrogate Podocyte NLRP3 Inflammasome Activation and Glomerular Inflammation during Obesity. J Pharmacol Exp Ther. 392(12):103757, 2025. PMCID: PMC13165501

Back to Listing