Abstract
Programmed death 1 (PD-1) is a novel member of the CD28/cytotoxic T-lymphocyte-associated protein-4 superfamily, which plays an important role in the regulation of activated T cells. However, it is not clear how PD-1 is expressed in normal and diseased kidney, nor if it has a role in progression of chronic renal disease. PD-1 expression and the effect of monoclonal anti-PD-1 antibody (Ab) were examined in murine adriamycin nephropathy (AN). BALB/c mice were divided into three groups: (a) normal mice, (b) adriamycin (ADR) with control immunoglobulin (Ig)G (ADR-IgG), and (c) ADR with anti-PD-1 Ab (ADR-Ab). AN was induced by a single intravenous injection of ADR. Anti-PD-1 Ab was given by intraperitoneal injection on alternate days from day 0 to day 10, or to day 18. Animals were killed at week 4. Renal function, histological change, and cytokine expression were examined. PD-1 mRNA was detected in kidney tissue of mice with AN in a dose- and time-dependent manner. PD-1 was mainly expressed on injured tubule cells and some interstitial cells, which co-stained with alpha-smooth muscle actin in AN, but not in normal kidney. Anti-PD-1 treatment up to day 18, but not to day 10, worsened glomerular and tubulointerstitial injury. The ratio of urinary protein/creatinine was significantly higher in ADR-Ab mice than ADR-IgG mice. The number of macrophages was significantly increased in ADR-Ab mice compared with ADR-IgG mice. Blockade of PD-1 worsened progressive renal histopathological and functional injury in murine AN. This suggests a possible protective role for PD-1 in chronic renal disease, and its potential as a treatment to slow disease progression.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / immunology
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Animals
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Antibodies, Monoclonal / immunology
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B7-1 Antigen / administration & dosage
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B7-1 Antigen / genetics
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B7-1 Antigen / immunology*
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B7-1 Antigen / physiology
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B7-H1 Antigen
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Creatinine / urine
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Cricetinae
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Data Interpretation, Statistical
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Disease Models, Animal
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Disease Progression
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Dose-Response Relationship, Drug
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Doxorubicin* / administration & dosage
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Enzyme-Linked Immunosorbent Assay
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Fluorescent Antibody Technique
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Glomerulosclerosis, Focal Segmental / chemically induced
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Glomerulosclerosis, Focal Segmental / genetics
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Glomerulosclerosis, Focal Segmental / immunology
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Glomerulosclerosis, Focal Segmental / metabolism
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Glomerulosclerosis, Focal Segmental / pathology*
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Glomerulosclerosis, Focal Segmental / therapy
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Immunoglobulin G / immunology
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Immunoglobulins / immunology
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Immunohistochemistry
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Injections, Intraperitoneal
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Injections, Intravenous
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Kidney Failure, Chronic / chemically induced
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Kidney Failure, Chronic / genetics
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Kidney Failure, Chronic / immunology
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Kidney Failure, Chronic / metabolism
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Kidney Failure, Chronic / pathology*
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Kidney Failure, Chronic / therapy
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Kidney Glomerulus / pathology
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Kidney Tubules / pathology
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Macrophages
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred C57BL
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Peptides / administration & dosage
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Peptides / genetics
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Peptides / immunology*
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Peptides / physiology
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Proteinuria / diagnosis
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RNA, Messenger / analysis
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Reverse Transcriptase Polymerase Chain Reaction
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Staining and Labeling / methods
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Time Factors
Substances
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Actins
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Antibodies, Monoclonal
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B7-1 Antigen
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B7-H1 Antigen
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Cd274 protein, mouse
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Immunoglobulin G
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Immunoglobulins
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Membrane Glycoproteins
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Peptides
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RNA, Messenger
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Doxorubicin
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Creatinine