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Article ; Online: Effects of the complement system on antibody formation and function: implications for transplantation.

Cumpelik, Arun / Heeger, Peter S

Current opinion in organ transplantation

2022 Volume 27, Issue 5, Page(s) 399–404

Abstract: Purpose of review: In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein ...

Abstract	Purpose of review: In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein we review recent data that describes how complement affects antibody formation and we discuss therapeutic implications. Recent findings: Extravasating T cells interacting with integrins express and activate intracellular complement that drives immune-metabolic adaptations vital for CD4 + helper cells. Marginal zone B cells can acquire intact major histocompatibility complexes from dendritic cells via complement-dependent trogocytosis for presentation to T cells. Activated B cells in germinal centers receive co-stimulatory signals from T-helper cells. These germinal center B cells undergo coordinate shifts in surface complement regulator expression that permit complement receptor signaling on the germinal center B cells required for affinity maturation. The positively selected, high-affinity B cells can differentiate into plasma cells that produce donor-HLA-reactive antibodies capable of ligating endothelial, among other, graft cells. Subsequent sublytic complement attack can stimulate endothelial cells to activate CD4 + and CD8 + T cells, promoting cellular and humoral rejection. Newly developed complement inhibitors are being tested to prevent/treat transplant rejection. Summary: The complement system influences T-cell, B-cell and endothelial-cell activation, and thereby contributes allograft injury. Emerging therapeutic strategies targeting complement activation have the potential to prevent or abrogate transplant injury and improve transplant outcomes.
MeSH term(s)	Antibody Formation ; Complement System Proteins ; Endothelial Cells/metabolism ; Graft Rejection/prevention & control ; Humans ; Isoantibodies
Chemical Substances	Isoantibodies ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2022-07-15
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1390429-2
ISSN	1531-7013 ; 1087-2418
ISSN (online)	1531-7013
ISSN	1087-2418
DOI	10.1097/MOT.0000000000001002
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Article ; Online: Enabling Clinical Trials for AMR in the Era of Precision Medicine.

Cumpelik, Arun / Zhang, Zhongyang / Menon, Madhav C

Transplantation

2020 Volume 105, Issue 3, Page(s) 482–483

MeSH term(s)	Precision Medicine
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000003275
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Article ; Online: Cutting Edge: Neutrophil Complement Receptor Signaling Is Required for BAFF-Dependent Humoral Responses in Mice.

Cumpelik, Arun / Cody, Evan / Yu, Samuel Mon-Wei / Grasset, Emilie K / Dominguez-Sola, David / Cerutti, Andrea / Heeger, Peter S

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 210, Issue 1, Page(s) 19–23

Abstract: T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, but mechanisms effectively linking neutrophil activation ... ...

Abstract	T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, but mechanisms effectively linking neutrophil activation to TI B cell responses are incompletely understood. Using germline and conditional knockout mice, we found that TI humoral responses involve alternative pathway complement activation and neutrophil-expressed C3a and C5a receptors (C3aR1/C5aR1) that promote BAFF-dependent B1 cell expansion and TI Ab production. Conditional absence of C3aR1/C5aR1 on neutrophils lowered serum BAFF levels, led to fewer Peyer's patch germinal center B cells, reduced germinal center B cells IgA class-switching, and lowered fecal IgA levels. Together, the results indicate that sequential activation of complement on neutrophils crucially supports humoral TI and mucosal IgA responses through upregulating neutrophil production of BAFF.
MeSH term(s)	Mice ; Animals ; Neutrophils ; B-Lymphocytes ; Complement System Proteins/metabolism ; Mice, Knockout ; Receptors, Complement/metabolism ; Immunoglobulin A
Chemical Substances	Complement System Proteins (9007-36-7) ; Receptors, Complement ; Immunoglobulin A
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200410
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Article ; Online: Mannan-Binding Lectin Promotes Murine Graft-versus-Host Disease by Amplifying Lipopolysaccharide-Initiated Inflammation.

Heja, David / Zhao, Dongchang / Cody, Evan / Cumpelik, Arun / Lim, Pik Chin / Prado-Acosta, Mariano / Palma, Liv / Dellepiane, Sergio / Chun, Nicholas / Ferrara, James / Heeger, Peter S

Transplantation and cellular therapy

2022 Volume 28, Issue 8, Page(s) 472.e1–472.e11

Abstract: Conditioning regimens used for hematopoietic stem cell transplantation (HCT) can escalate the severity of acute T cell-mediated graft-versus-host disease (GVHD) by disrupting gastrointestinal integrity and initiating lipopolysaccharide (LPS)-dependent ... ...

Abstract	Conditioning regimens used for hematopoietic stem cell transplantation (HCT) can escalate the severity of acute T cell-mediated graft-versus-host disease (GVHD) by disrupting gastrointestinal integrity and initiating lipopolysaccharide (LPS)-dependent innate immune cell activation. Activation of the complement cascade has been associated with murine GVHD, and previous work has shown that alternative pathway complement activation can amplify T cell immunity. Whether and how mannan-binding lectin (MBL), a component of the complement system that binds mannose as well as oligosaccharide components of LPS and lipoteichoic acid, affects GVHD is unknown. In this study, we tested the hypothesis that MBL modulates murine GVHD and examined the mechanisms by which it does so. We adoptively transferred C3.SW bone marrow (BM) cells ± T cells into irradiated wild type (WT) or MBL-deficient C57Bl/6 (B6) recipients with or without inhibiting MBL-initiated complement activation using C1-esterase inhibitor (C1-INH). We analyzed the clinical severity of disease expression and analyzed intestinal gene and cell infiltration. In vitro studies assessed MBL expression on antigen-presenting cells (APCs) and compared LPS-induced responses of WT and MBL-deficient APCs. MBL-deficient recipients of donor BM ± T cells exhibited significantly less weight loss over the first 2 weeks post-transplantation weeks compared with B6 controls (P < .05), with similar donor engraftment in the 2 groups. In recipients of C3.SW BM + T cells, the clinical expression of GVHD was less severe (P < .05) and overall survival was better (P < .05) in MBL-deficient mice compared with WT mice. On day-7 post-transplantation, analyses showed that the MBL-deficient recipients exhibited less intestinal IL1b, IL17, and IL12 p40 gene expression (P < .05 for each) and fewer infiltrating intestinal CD11c
MeSH term(s)	Animals ; Bone Marrow Transplantation ; CD8-Positive T-Lymphocytes ; Graft vs Host Disease/genetics ; Inflammation/etiology ; Inflammation/genetics ; Lipopolysaccharides/adverse effects ; Lipopolysaccharides/pharmacology ; Mannose-Binding Lectin/genetics ; Mice ; Mice, Inbred C57BL ; Transplantation, Homologous
Chemical Substances	Lipopolysaccharides ; Mannose-Binding Lectin ; mannose binding protein A (143107-68-0)
Language	English
Publishing date	2022-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2022.05.031
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Article ; Online: Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome.

Cumpelik, Arun / Ankli, Barbara / Zecher, Daniel / Schifferli, Jürg A

Annals of the rheumatic diseases

2016 Volume 75, Issue 6, Page(s) 1236–1245

Abstract: Objectives: Gout is a highly inflammatory but self-limiting joint disease induced by the precipitation of monosodium urate (MSU) crystals. While it is well established that inflammasome activation by MSU mediates acute inflammation, little is known ... ...

Abstract	Objectives: Gout is a highly inflammatory but self-limiting joint disease induced by the precipitation of monosodium urate (MSU) crystals. While it is well established that inflammasome activation by MSU mediates acute inflammation, little is known about the mechanism controlling its spontaneous resolution. The aim of this study was to analyse the role of neutrophil-derived microvesicles (PMN-Ecto) in the resolution of acute gout. Methods: PMN-Ecto were studied in a murine model of MSU-induced peritonitis using C57BL/6, MerTK(-/-) and C5aR(-/-) mice. The peritoneal compartment was assessed for the number of infiltrating neutrophils (PMN), neutrophil microvesicles (PMN-Ecto), cytokines (interleukin-1β, TGFβ) and complement factors (C5a). Human PMN-Ecto were isolated from exudates of patients undergoing an acute gouty attack and functionally tested in vitro. Results: C5a generated after the injection of MSU primed the inflammasome for IL-1β release. Neutrophils infiltrating the peritoneum in response to C5a released phosphatidylserine (PS)-positive PMN-Ecto early on in the course of inflammation. These PMN-Ecto in turn suppressed C5a priming of the inflammasome and consequently inhibited IL-1β release and neutrophil influx. PMN-Ecto-mediated suppression required surface expression of the PS-receptor MerTK and could be reproduced using PS-expressing liposomes. In addition, ectosomes triggered the release of TGFβ independent of MerTK. TGFβ, however, was not sufficient to control acute MSU-driven inflammation in vivo. Finally, PMN-Ecto from joint aspirates of patients with gouty arthritis had similar anti-inflammatory properties. Conclusions: PMN-Ecto-mediated control of inflammasome-driven inflammation is a compelling concept of autoregulation initiated early on during PMN activation in gout.
MeSH term(s)	Acute Disease ; Animals ; Cell-Derived Microparticles/physiology ; Cell-Derived Microparticles/transplantation ; Cells, Cultured ; Complement C5a/biosynthesis ; Complement C5a/immunology ; Cytokines/metabolism ; Gout/immunology ; Gout/metabolism ; Gout/pathology ; Humans ; Inflammasomes/immunology ; Inflammasomes/metabolism ; Inflammasomes/physiology ; Liposomes/metabolism ; Mice, Inbred C57BL ; Neutrophil Activation/physiology ; Neutrophil Infiltration/physiology ; Neutrophils/physiology ; Peritonitis/immunology ; Peritonitis/pathology ; Phosphatidylserines/metabolism
Chemical Substances	Cytokines ; Inflammasomes ; Liposomes ; Phosphatidylserines ; Complement C5a (80295-54-1)
Language	English
Publishing date	2016-06
Publishing country	England
Document type	Journal Article
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/annrheumdis-2015-207338
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Article ; Online: Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement.

Zecher, Daniel / Cumpelik, Arun / Schifferli, Jürg A

Arteriosclerosis, thrombosis, and vascular biology

2014 Volume 34, Issue 2, Page(s) 313–320

Abstract: Objective: Transfusion of aged blood has been associated with increased morbidity and mortality in critically ill patients. During storage, erythrocytes release increasing numbers of microvesicles (red blood cell-derived microvesicles [RBC-MV]). We ... ...

Abstract	Objective: Transfusion of aged blood has been associated with increased morbidity and mortality in critically ill patients. During storage, erythrocytes release increasing numbers of microvesicles (red blood cell-derived microvesicles [RBC-MV]). We hypothesized that RBC-MV mediate some of the deleterious effects of aged blood transfusions. Approach and results: We established a murine transfusion model using RBC-MV purified from aged mouse erythrocytes. Injection of RBC-MV into healthy mice had no effect. However, they aggravated pulmonary leukocyte sequestration and peripheral blood leukopenia induced by lipopolysaccharides. Lipopolysaccharide-induced proinflammatory cytokines were significantly increased in plasma after RBC-MV injection. These effects were not seen in C5aR-deficient mice. In vitro, RBC-MV bound C3 fragments after incubation with plasma but failed to bind immunoglobulins, C1q, or mannose-binding lectin. Preventing thrombin generation inhibited complement activation in vitro and in vivo and reversed the proinflammatory effects of RBC-MV in lipopolysaccharide-primed mice. Finally, the RBC-MV-induced phenotype was recapitulated using phosphatidylserine-expressing liposomes, suggesting that surface expression of phosphatidylserine by RBC-MV was mechanistically involved. Conclusions: These results point toward a thrombin-dependent mechanism of complement activation by RBC-MV independent of the classical, lectin, or alternative pathway. Besides identifying RBC-MV as potential mediators of transfusion-related morbidity, our findings may be relevant for other inflammatory disorders involving intravascular microvesicle release, for example, sickle cell disease or thrombotic microangiopathy.
MeSH term(s)	Animals ; Cell-Derived Microparticles/immunology ; Cell-Derived Microparticles/metabolism ; Complement Activation ; Complement C3/immunology ; Complement C3/metabolism ; Erythrocyte Transfusion/adverse effects ; Erythrocytes/immunology ; Erythrocytes/metabolism ; Genotype ; Inflammation/blood ; Inflammation/chemically induced ; Inflammation/immunology ; Leukopenia/blood ; Leukopenia/immunology ; Lipopolysaccharides ; Liposomes ; Lung/immunology ; Lung/metabolism ; Mice ; Mice, 129 Strain ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Animal ; Neutrophil Infiltration ; Peptide Fragments/immunology ; Peptide Fragments/metabolism ; Phenotype ; Phosphatidylserines/immunology ; Phosphatidylserines/metabolism ; Receptor, Anaphylatoxin C5a/deficiency ; Receptor, Anaphylatoxin C5a/genetics ; Thrombin/immunology ; Thrombin/metabolism ; Time Factors
Chemical Substances	Complement C3 ; Lipopolysaccharides ; Liposomes ; Peptide Fragments ; Phosphatidylserines ; Receptor, Anaphylatoxin C5a ; lipopolysaccharide, E coli O55-B5 ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2014-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.113.302378
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Article ; Online: Erythropoietin Reduces Auto- and Alloantibodies by Inhibiting T Follicular Helper Cell Differentiation.

Guglielmo, Chiara / Bin, Sofia / Cantarelli, Chiara / Hartzell, Susan / Angeletti, Andrea / Donadei, Chiara / Cumpelik, Arun / Anderson, Lisa / Cody, Evan / Sage, Peter T / La Manna, Gaetano / Fiaccadori, Enrico / Heeger, Peter S / Cravedi, Paolo

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 10, Page(s) 2542–2560

Abstract: Background: Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has ... ...

Abstract	Background: Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown. Methods: We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent antibody formation using Results: In wild-type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (T Conclusions: Our findings newly demonstrate that EPO inhibits T
MeSH term(s)	Animals ; Antibody Formation/drug effects ; B-Lymphocytes/immunology ; CD4 Lymphocyte Count ; Cell Differentiation/drug effects ; Cells, Cultured ; Erythropoietin/genetics ; Erythropoietin/metabolism ; Erythropoietin/pharmacology ; Female ; Humans ; Immunity, Humoral/drug effects ; Male ; Mice ; Phosphorylation ; Receptors, Erythropoietin/metabolism ; STAT5 Transcription Factor/metabolism ; Signal Transduction ; T Follicular Helper Cells/immunology ; T Follicular Helper Cells/metabolism ; T Follicular Helper Cells/physiology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Receptors, Erythropoietin ; STAT5 Transcription Factor ; Stat5a protein, mouse ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2021-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2021010098
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Article ; Online: Dynamic regulation of B cell complement signaling is integral to germinal center responses.

Cumpelik, Arun / Heja, David / Hu, Yuan / Varano, Gabriele / Ordikhani, Farideh / Roberto, Mark P / He, Zhengxiang / Homann, Dirk / Lira, Sergio A / Dominguez-Sola, David / Heeger, Peter S

Nature immunology

2021 Volume 22, Issue 6, Page(s) 757–768

Abstract: Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity- ... ...

Abstract	Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by mechanisms hitherto incompletely understood. Here we found that, as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3 convertase regulators via BCL6, but increased the expression of C5b-9 inhibitor CD59. These changes permitted C3 cleavage on GC B cell surfaces without the formation of membrane attack complex and activated C3a- and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors limited the activation of mechanistic target of rapamycin (mTOR) in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.
MeSH term(s)	Animals ; Animals, Genetically Modified ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; CD55 Antigens/genetics ; CD55 Antigens/metabolism ; CD59 Antigens/metabolism ; Cell Line, Tumor ; Clonal Hematopoiesis/immunology ; Complement Activation ; Complement C3a/metabolism ; Complement C5a/metabolism ; Germinal Center/cytology ; Germinal Center/immunology ; Germinal Center/metabolism ; Humans ; Lymphocyte Activation ; Mice ; Palatine Tonsil/cytology ; Palatine Tonsil/pathology ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Receptor, Anaphylatoxin C5a/genetics ; Receptor, Anaphylatoxin C5a/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Receptors, Complement/genetics ; Receptors, Complement/metabolism ; Signal Transduction/immunology ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	CD55 Antigens ; CD59 Antigens ; Proto-Oncogene Proteins c-bcl-6 ; Receptor, Anaphylatoxin C5a ; Receptors, Antigen, B-Cell ; Receptors, Complement ; complement C3a receptor ; Complement C3a (80295-42-7) ; Complement C5a (80295-54-1) ; MTOR protein, human (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-021-00926-0
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Article ; Online: AMPK mediates regulation of glomerular volume and podocyte survival.

Banu, Khadija / Lin, Qisheng / Basgen, John M / Planoutene, Marina / Wei, Chengguo / Reghuvaran, Anand C / Tian, Xuefei / Shi, Hongmei / Garzon, Felipe / Garzia, Aitor / Chun, Nicholas / Cumpelik, Arun / Santeusanio, Andrew D / Zhang, Weijia / Das, Bhaskar / Salem, Fadi / Li, Li / Ishibe, Shuta / Cantley, Lloyd G /

Kaufman, Lewis / Lemley, Kevin V / Ni, Zhaohui / He, John Cijiang / Murphy, Barbara / Menon, Madhav C

JCI insight

2021 Volume 6, Issue 19

Abstract: Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human ... ...

Abstract	Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.
MeSH term(s)	Adenylate Kinase/antagonists & inhibitors ; Adenylate Kinase/metabolism ; Adolescent ; Adult ; Aged ; Albuminuria/genetics ; Animals ; Cell Size ; Cell Survival/genetics ; Child ; Child, Preschool ; Female ; Gene Knockdown Techniques ; Glomerulonephritis, Membranous/genetics ; Glomerulonephritis, Membranous/pathology ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/pathology ; Humans ; Hypertrophy ; Infant ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Male ; Mice ; Microfilament Proteins/genetics ; Middle Aged ; Nephrectomy ; Nephrosis, Lipoid/genetics ; Nephrosis, Lipoid/pathology ; Nephrotic Syndrome/genetics ; Nephrotic Syndrome/pathology ; Podocytes/metabolism ; Podocytes/pathology ; Proportional Hazards Models ; Proto-Oncogene Proteins c-fyn/genetics ; Young Adult
Chemical Substances	Microfilament Proteins ; Shrm protein, mouse ; FYN protein, human (EC 2.7.10.2) ; Fyn protein, mouse (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2) ; Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2021-10-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.150004
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Article ; Online: AMPK mediates regulation of glomerular volume and podocyte survival

JCI Insight, Vol 6, Iss

2021 Volume 19

Abstract	Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.
Keywords	Cell biology ; Nephrology ; Medicine ; R
Subject code	616
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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