IFN-inducible protein-10 plays a pivotal role in maintaining slit-diaphragm function by regulating podocyte cell-cycle balance.
IFN-inducible protein-10 (IP-10/CXCL10) is a potent chemoattractant for activated T lymphocytes and was reported recently to have several additional biologic activities. In this study, the pathophysiologic role of IP-10 in the glomerular visceral epithelial cell (podocyte) was investigated. In cultured podocytes subjected to recombinant IP-10 treatment, the expression of slit-diaphragm (SD) components nephrin and podocin clearly was heightened. Rats that had puromycin aminonucleoside nephropathy and anti-nephrin antibody-induced nephropathy and were subjected to anti-IP-10 function-blocking antibody (anti-IP-10 mAb) treatment displayed a decrease in the protein level of SD components, as well as exacerbated proteinuria. For exploration of the mechanisms of this process, the interaction between IP-10 and the cell-cycle regulatory proteins was investigated. Cultured podocytes subjected to recombinant IP-10 treatment displayed an increase in the protein level of p27(Kip1), whereas the levels of cyclins E and A decreased. The expression of IP-10 and SD components was heightened by the treatment of siRNA of cyclin A, whereas these expressions were lowered by the treatment of siRNA of p27(Kip1). Proteinuric rats subjected to anti-IP-10 mAb treatment displayed a heightened expression of cyclin A from the early phase of the disease, which indicates that the anti-IP-10 mAb treatment exacerbates podocyte injury by disturbing the cell-cycle balance. These results raise the possibility that IP-10 could become a novel therapeutic target in nephrotic syndrome and several diseases with altered cell-cycle balance.
Han
Gi Dong
GD
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan.
Suzuki
Koichi
K
Koike
Hiroko
H
Suzuki
Kenji
K
Yoneyama
Hiroyuki
H
Narumi
Shosaku
S
Shimizu
Fujio
F
Kawachi
Hiroshi
H
D000818:Animals; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000502:physiology*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D050199:Podocytes / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C091326:Cxcl10 protein, rat; C515189:Cxcr3 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; C113267:nephrin