IFN-inducible protein-10 plays a pivotal role in maintaining slit-diaphragm function by regulating podocyte cell-cycle balance.

Abstract

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.

• Authors: Gi Dong Han, Koichi Suzuki, Hiroko Koike, Kenji Suzuki, Hiroyuki Yoneyama, Shosaku Narumi, Fujio Shimizu, Hiroshi Kawachi
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 17 Issue 2 Pg. 442-53 (Feb 2006) ISSN: 1046-6673 [Print] United States
• PMID: 16382022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL10
• Chemokines, CXC
• Cxcl10 protein, rat
• Cxcr3 protein, rat
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• NPHS2 protein
• Receptors, CXCR3
• Receptors, Chemokine
• nephrin

Topics

• Animals
• Cell Culture Techniques
• Cell Cycle (physiology)
• Chemokine CXCL10
• Chemokines, CXC (physiology)
• Disease Models, Animal
• Female
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins (metabolism)
• Nephrotic Syndrome (metabolism, physiopathology)
• Podocytes (cytology)
• Rats
• Rats, Wistar
• Receptors, CXCR3
• Receptors, Chemokine (metabolism)