Pin-Lan Li, M.D., Ph.D.

Professor and Vice Chair

Pin-Lan Li, M.D., Ph.D.Director for Hypertension and Kidney Research Arthur and Margaret Glasgow Chair

Department: Department of Pharmacology and Toxicology

Phone: (804) 828-4793

Fax: (804) 828-2117

Email: pin-lan.li@vcuhealth.org

Address/Location:
Molecular Medicine Research Building, Room 3050
1220 East Broad Street
Box 980613
Richmond, Virginia

Education

  • Yichang Medical College, China, M.D., 1975
  • University of Heidelberg, Germany, Ph.D., 1992

Research interests

  • Molecular mechanisms of podocytopathy and associated hypertension.
  • Blood pressure regulation by endocannabinoid and exosomes in the renal medulla.
  • Lipid raft redox signaling platforms in coronary endothelial cells.
  • Inflammasome activation in hyperhomocysteinemia-induced glomerular disease.
  • Novel second messengers – cADP-ribose and NAADP in arterial myocytes

Research in my laboratory mainly deals with pathogenesis of renal glomerular injury associated with hyperhomocysteinemia and hypertension and with the cell and molecular regulation of coronary circulation. Some specific projects and approaches are as follows:

Molecular mechanisms of podocytopathy and associated hypertension. We have recently worked to explore the mechanisms by which lysosome function is fine regulated for exosome release, which mediates cell-to-cell communications in different tissues or organs. Exosomes in cells are formed as intraluminal vesicles (ILV) of multiple vesicular bodies (MVBs) via endocytic process. MVBs can fuse with and deliver content to lysosomes for degradation or fuse with plasma membrane to release ILVs as exosomes. Lysosome trafficking to and fusion with MVBs were demonstrated to control exosome secretion in renal podocytes, which were mediated by a lysosomal enzyme, acid ceramidase (AC) and associated sphingolipids signaling. The AC gene (code ASAH1) or deficiency of lysosomal AC activity (metabolizing ceramide to sphingosine) is a pathogenic mechanism podocytopathy such as minimal change disease in the kidney. A paper entitled "Podocytopathy and Nephrotic Syndrome in Mice with Podocyte-Specific Deletion of the Asah1 Gene: Role of Ceramide Accumulation in Glomeruli" has been published on American Journal of Pathology, which was highlighted by an editorial commentary, which applauded that our finding "represents a new paradigm of research in which new insights may be born."

Blood pressure regulation by telocyte endocannabinoid and exosomes in the renal medulla. Our research has significantly advanced the understanding of renomedullary antihypertensive mechanisms and the long-sought identity of “medullipin.” We demonstrated that anandamide and its cyclooxygenase-2–derived metabolite, prostamide E₂, are enriched in the renal medulla and act as potent diuretic, natriuretic, and vasodepressor factors. We further showed that selective inhibition of fatty acid amide hydrolase (FAAH) in the renal medulla enhances renal excretory function and lowers arterial pressure through accumulation of endocannabinoids, defining a new pathway for blood pressure regulation. Extending this work to cultured mouse medullary interstitial cells, we identified a novel neutral lipid secreted in response to FAAH inhibition that exerts strong diuretic, natriuretic, and vasodepressor activity, supporting the concept that renomedullary lipids function as active mediators of cardiovascular homeostasis. More recently, we discovered that renomedullary exosomes serve as carriers of antihypertensive neutral lipids, mediating blood pressure reduction and diuresis during renovascular hypertension and reperfusion. A newly characterized renal medullary cells, Telocytes are found to play a critical role in mediating exosome release and renal medullary antihypertensive action. Collectively, our research will establish a new paradigm linking endocannabinoid metabolism, lipid mediators, and exosome biology in the renal medullary telocytes to the long-term regulation of body fluid balance and arterial pressure, thereby providing novel mechanistic insight into endogenous antihypertensive systems.

Lipid raft redox signaling platforms in coronary endothelial cells. My laboratory identified the role of lipid rafts for redox signaling and for the first time described lipid rafts-associated redox signaling platforms in coronary endothelial cells, which are now referred to as lipid raft redox signaling platforms. The first paper we published in this area was honored with an editorial commentary of Hypertension to commended that “the topic of lipid raft signaling is now taking center stage in endothelial cell redox signaling by death receptors.” Beyond studies on redox signaling, we also demonstrated the lipid raft signaling platforms in mediating the signal transduction of several other receptors, for instance, CD95, TNF-alpha receptor and endostatin targets. This concept of lipid raft signaling redox signaling platforms has been extended to some disease model with results indicating that derangement of lipid raft redox signaling may contribute to the development of cardiovascular disease such as atherosclerosis.

Inflammasome activation in hyperhomocysteinemia-induced glomerular disease. Hyperhomocysteinemia (hHcy) is a novel risk factor or pathogenic factor for various degenerative diseases such as atherosclerosis, Alzheimer disease and glomerular sclerosis associated with hypertension. Our laboratory provided the first experimental evidence indicating that NLRP3 inflammasome activation is importantly involved in hHcy-induced podocyte injury and glomerular sclerosis. This NLRP3 inflammasome activation not only turns on classical sterile inflammatory response including recruitment or aggregation of inflammatory cells in glomeruli such as macrophages and T-cells, but also directly acts on podocytes to cause damage. We explored the mechanisms by which NLRP3 inflammasome activation alters the functional and structural integrity of podocytes such as interfering with synthesis of podocyte-specific proteins, production of damage-associated molecular patterns and pyroptosis, which are independent of its action to instigate classical inflammatory response. It is believed that our findings reveal early initiating mechanisms of podocyte and glomerular injury during hHcy, which has shifted the paradigm in understanding hHcy-induced degenerative diseases and identifying therapeutic targets for treatment or prevention of these diseases.

Novel second messengers – cADP-ribose and NAADP in arterial myocytes. We are the first to characterize a novel intracellular second messenger, cyclic ADP-ribose (cADPR) in arterial myocytes and demonstrated that this cADPR serves as a second messenger to mediate intracellular Ca2+ mobilization independent of IP3 signaling pathway, but through ryanodine receptors. Our findings importantly define this signaling pathway that mediates Ca2+-induced Ca2+release, which serves a basic mechanism for maintenance of vascular tone, an under-studied area before our publications. In addition, we provided the first evidence demonstrating that a Ca2+release channel is present in lysosomes that is activated by cADPR analog, NAADP. This lysosomal Ca2+ release channel is mucolipin-1, a transient receptor potential (TRP) channel, namely, TRP-mucolipin 1 (TRPML1). A new concept has been established through our studies that lysosomal TRPML1 channel activity and its regulatory mechanism actively control lysosome function including its trafficking, fusion, and degradation.

Selected publications

  1. Li G, Kidd J, Kaspar C, Dempsey S, Bhat OM, Ritter J, Gehr TWB, Gulbins E, Li PL. Podocytopathy and nephrotic syndrome in mice with podocyte-specific deletion of Asah1 gene: Role of ceramide accumulation in glomeruli. Am J Pathol. 190(6):1211-1223, 2020 PMCID: PMC7280759 (with an Editorial Commentory. Am J Pathol. 190:1172-1174, 2020).
  2. Huang D, Li G, Zhang Q, Bhat OM, Zou Y, Ritter JK, Li PL. Contribution of Podocyte Inflammatory Exosome Release to Glomerular Inflammation and Sclerosis during Hyperhomocysteinemia. Biochim Biophys Acta Mol Basis Dis. 1867(7):166146, 2021. PMCID: PMC8122080
  3. Hu G, Li G, Huang D, Zou Y, Yuan X, Ritter JK, Li N, Li PL. Renomedullary exosomes produce antihypertensive effects in reversible two-kidney one-clip renovascular hypertensive mice. Biochem Pharmacol. 204:115238, 2022. PMCID: PMC10777442
  4. Yuan X, Bhat OM, Zou Y, Li X, Zhang Y, Li PL. Endothelial Acid Sphingomyelinase Promotes NLRP3 Inflammasome and Neointima Formation During Hypercholesterolemia. J Lipid Res. 63(12):100298, 2022. PMCID: PMC9672920
  5. 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
  6. Xia M, Abais JM, Boini KM, Li PL. Characterization and activation of NLRP3 inflammasomes in the renal medulla in mice. Kidney Blood Press Res. 41:208-221, 2016. PMCID: PMC4824620.
  7. Boini KM, Xia M, Koka S, Gehr T, Li PL. Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: Role of acid sphingomyelinase gene. Oncotarget. 7:19031-19044, 2016. PMCID: PMC4951349
  8. Chen Y, Yuan M, Xia M, Wang L, Zhang Y, Li PL. Instant membrane resealing in NLRP3 inflammmasome activation of endothelial cells. Front Biosci (Landmark Ed). 21:635-650, 2016. PMCID: PMC5507337
  9. Bao JX, Zhang QF, Wang M, Boini KM, Gulbins E, Zhang Y, Li PL. Implication of CD38 gene in autophagic degradation of collagen I in mouse coronary arterial myocytes. Front Biosci. (Landmark Ed), 22:558-569, 2017. PMCID: PMC5509348
  10. Conley SM, Abais-Batted JM, Yuan X, Zhang Q, Boini KM, Li PL. Contribution of guanine nucleotide exchange factor vav2 to NLRP3 inflammasome activation in mouse podocytes during hyperhomcysteinemia. Free Radic Biol Med. 106:236-244, 2017. PMCID: PMC5423457
  11. Li G, Chen Z, Bhat OM, Zhang Q, Abais-Batad J, Conley SM, Ritter J, Li PL. NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. J Lipid Res. 58:1080-1090, 2017. PMCID: PMC5454504
  12. Koka S, Xia M, Chen Y, Bhat OM, Yuan X, Boini KM, Li PL. Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. Redox Biol. 13:336-344, 2017. PMCID: PMC5479959
  13. Yuan X, Wang L, Bhat OM, Lohner H, Li PL. Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate. Redox Biol. 16:21-31, 2018. PMCID: PMC5842312
  14. Bhat OM, Yuan X, Li G, Lee R, Li PL. Sphingolipids and redox signaling in renal regulation and chronic kidney diseases. Antioxid Redox Signal. 28:1008–1026, 2018. PMCID: PMC5849286
  15. Li PL, Gulbins E. Bioactive lipids and redox signaling: Molecular mechanism and disease pathogenesis. Antioxid Redox Signal. 28:911–915 2018. PMCID: PMC5849277
  16. 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. BBA-Mol Cell Biol Lipids. 1863:1246-1256, 2018. PMCID: PMC618094
  17. Yuan X, Bhat OM, Meng N, Lohner H, Li PL. Protective role of autophagy in Nlrp3 inflammasome activation and medial thickening of mouse coronary arteries. Am J Pathol. 188:2948-2959, 2018. PMCID: PMC6334256
  18. Yuan X, Bhat OM, Lohner H, Li N, Zhang Y, Li PL. Inhibitory effects of growth differentiation factor 11 on autophagy deficiency-induced dedifferentiation of arterial smooth muscle cells. Am J Physiol Heart Circ Physiol. 316:H345-H356, 2019. PMCID: PMC639738
  19. Hong J, Bhat OM, Li G, Dempsey SK, Zhang Q, Ritter JK, Li W, Li PL. Lysosomal regulation of extracellular vesicle excretion during D-Ribose-induced NLRP3 inflammasome activation in podocytes. BBA-Mol Cell Res. 1866:849-860, 2019. PMID: 30771382
  20. Zhang Q, Conley SM, Li G, Yuan X, Li PL. Rac1 GTPase inhibition blocked podocyte injury and glomerular sclerosis during hyperhomocysteinemia via suppression of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 inflammasome activation. Kidney Blood Press Res. 2019 Jul 2:1-20. doi: 10.1159/000500457. [Epub ahead of print]
  21. 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. 2019 Jul 3. doi: 10.1152/ajpcell.00150.2019. [Epub ahead of print]

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