A protective role for programmed death 1 in progression of murine adriamycin nephropathy.
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.
Qin
X H
XH
Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Lee
V W S
VW
Wang
Y P
YP
Zheng
G P
GP
Wang
Y
Y
Alexander
S I
SI
Harris
D C H
DC
D000199:Actins / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D060890:B7-H1 Antigen; D003404:Creatinine / Q000652:urine; D006224:Cricetinae; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000276:immunology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008264:Macrophages; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D011507:Proteinuria / Q000175:diagnosis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors
D000199:Actins; D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007074:Immunoglobulin G; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D004317:Doxorubicin; D003404:Creatinine