Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome.
Several recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the principal barrier in the glomerular capillary wall. Nephrin identified as a gene product mutated in congenital nephrotic syndrome located at the outer leaflet of plasma membranes of the slit diaphragm. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. Expression of nephrin was reduced in glomeruli of minimal change nephrotic syndrome. Some recent studies demonstrated that podocin, CD2-associated protein and NEPH1 are also functional molecules in the slit diaphragm, and their expressions are altered in membranous nephropathy and also in focal glomerulosclerosis. These observations suggested that the alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases. Recent studies of our group have demonstrated that type 1 receptor-mediated angiotensin II action reduced the expression of the slit diaphragm-associated molecules and that type 1 receptor blockade ameliorated proteinuria by preventing the function of angiotensin II on the slit diaphragm. By the subtraction hybridization techniques using glomerular cDNA of normal and proteinuric rats, we detected that synaptic vesicle protein 2B and ephrin B1 are involved in the maintenance of the barrier function of the slit diaphragm.
Kawachi
Hiroshi
H
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan. kawachi@med.niigata-u.ac.jp.
Suzuki
Koichi
K
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.
Miyauchi
Naoko
N
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.
Hashimoto
Taeko
T
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.
Otaki
Yasuhiro
Y
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.
Shimizu
Fujio
F
Niigata Seiryo University, Niigata, Japan.
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D036387:Ephrin-B1 / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D047228:Angiotensin II Type 1 Receptor Blockers; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D036387:Ephrin-B1; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D009419:Nerve Tissue Proteins; D044140:Receptor, Angiotensin, Type 1; C489617:Sv2b protein, rat; C113267:nephrin; D000804:Angiotensin II