Therapeutic targets in the podocyte: findings in anti-slit diaphragm antibody-induced nephropathy.
Recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Murine monoclonal antibody against nephrin, a molecule constituting the extracellular site of the slit diaphragm, caused severe proteinuria if injected into rats, in a complement- or inflammatory cell-independent manner. In this proteinuric state, not only nephrin but also other slit diaphragm-associated molecules are down-regulated. These observations suggest that the antibody alters the molecular composition of the slit diaphragm and, thereby, affects the glomerular permeability barrier. Recently, it was found that IP-10, SV2B, ephrin B1 and the receptors of angiotensin II were expressed in the podocyte, and that their expressions were clearly altered in anti-nephrin antibody-induced nephropathy. It is conceivable that these molecules are involved in the development of proteinuria in this model. IP-10 is assumed to play a role in maintaining the slit diaphragm function by regulating the cell cycle balance of the podocyte. SV2B and ephrin B1 play pivotal roles in the proper localization of the slit diaphragm component. In vivo and in vitro studies demonstrated that angiotensin II type 2 receptor-mediated action enhanced the expression of nephrin. We propose that these molecules could be novel therapeutic targets for proteinuria.
Kawachi
Hiroshi
H
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. kawachi@med.niigata-u.ac.jp
Han
Gi Dong
GD
Miyauchi
Naoko
N
Hashimoto
Taeko
T
Suzuki
Koichi
K
Shimizu
Fujio
F
D000818:Animals; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000502:physiology; D036387:Ephrin-B1 / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008565:Membrane Proteins / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D050199:Podocytes / Q000276:immunology*; D011507:Proteinuria / Q000209:etiology* / Q000628:therapy; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology
D054357:Chemokine CXCL10; D036387:Ephrin-B1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D044139:Receptor, Angiotensin, Type 2; C489616:SV2B protein, human; C113267:nephrin