Oxidized low-density lipoprotein antigen transport induces autoimmunity in the renal tubulointerstitium.
OBJECTIVE
Chronic kidney disease involves inflammation/oxidative stress, which contributes to progressive kidney injury.


METHODS
Male Sprague-Dawley rats underwent 5/6 nephrectomy (Nx) or sham Nx and were sacrificed after 2 days, 2 weeks and 4 weeks. Microarray analysis expression sets over time suggested the evolution of renal lymphocyte infiltration and antigen-presenting cell (APC) activation after 5/6Nx. RT-PCR analysis also confirmed the migration and activation of lymphocytes and APCs through the upregulation of CD3, CXCR3/CXCL10 and CCR7/CCL19 mRNA in remnant kidney (RK). Purified T lymphocytes from spleen and unilateral ureteral obstruction (UUO) kidney were incubated with oxidized low-density lipoprotein (Ox-LDL)-treated major histocompatibility complex class II (MHC II)-expressing APCs. Culture supernatant was collected for mouse IFN-γ ELISA and cell proliferation was measured.


RESULTS
Ox-LDL deposited predominantly in renal tubulointerstitial areas of RK, increased over time, and co-stained with lectin-like Ox-LDL receptor in affected renal tubular cells. Both Ox-LDL and renal-specific glycoprotein Tamm-Horsfall protein were identified in renal lymph nodes. Cells co-staining for major MHC II and Ox-LDL were observed in RK and draining renal lymph nodes after 5/6Nx. Similarly, Ox-LDL was also present in tubules after UUO, CD3-positive T cells were present in the interstitium, and Ox-LDL-treated MHC II-expressing APCs induced proliferation and IFN-γ production in renal tubulointerstitial T lymphocytes isolated from kidneys after UUO.


CONCLUSIONS
These data demonstrate that the tubulointerstitial inflammatory infiltrate that accompanies chronic kidney disease reflects, at least in part, the development of autoimmunity to novel antigens generated during renal injury.
Harbor-UCLA Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA.
Bancha
B
Satirapoj
Kevin W
KW
Bruhn
Cynthia C
CC
Nast
Ying
Y
Wang
Tiane
T
Dai
Janine
J
Lapage
Xiwei
X
Wu
Rama
R
Natarajan
Sharon G
SG
Adler
D000818:Animals; D015551:Autoimmunity; D017252:CD3 Complex / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D002908:Chronic Disease; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000494:pharmacology; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054400:Receptors, CCR7 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D014517:Ureteral Obstruction / Q000276:immunology; D058949:Uromodulin / Q000378:metabolism
C515460:CCL19 protein, human; C515370:CCR7 protein, human; D017252:CD3 Complex; C515187:CXCR3 protein, human; D054415:Chemokine CCL19; D054357:Chemokine CXCL10; D000949:Histocompatibility Antigens Class II; D008077:Lipoproteins, LDL; C495136:OLR1 protein, rat; D012333:RNA, Messenger; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D051127:Scavenger Receptors, Class E; C548614:Umod protein, rat; D058949:Uromodulin; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma