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Abstract
Nephrotic syndrome is caused by increased permeability of the glomerular capillary wall for proteins. The molecular pathogenesis of nephrotic proteinuria has still not been fully elucidated. Recently, mutations of several podocyte proteins have been identified as causes of familial nephrotic syndrome. This has led to progress in our understanding of the molecular structure of the slit diaphragm between podocyte foot processes and podocyte interaction with the glomerular basement membrane. Both the nephrin receptor complex at the slit diaphragm and integrin receptor that mediates binding of the podocyte to the glomerular basement membrane may mediate outside-inside signaling in the podocyte. Thus, the podocyte not only forms one of the barriers to protein permeability but also is a highly flexible dynamic system able to respond to injury. Recent progress in the knowledge of the structure and function of glomerular podocytes should result in the elucidation of the pathogenesis of nephrotic proteinuria in commonly acquired proteinuric diseases and should pave the way to new therapeutic approaches.
| Abbreviations | ||
| ACE | = | angiotensin converting enzyme |
| ACEI | = | angiotensin converting enzyme inhibitors |
| AGEs | = | advanced glycation end-products |
| Akt | = | serine-threonine-specific protein kinase, member of serine/threonine-specific protein kinase family, protein kinase B |
| ANP | = | atrial natriuretic peptide |
| AP-1 | = | activation protein-1 |
| Arp2/3 | = | actin-related proteins |
| ATP | = | adenosine triphosphate |
| AIIA | = | angiotensin II antagonists |
| bHLH | = | basic helix-loop-helix transcription factor |
| cAMP | = | cyclic adenosine monophosphate |
| CASK | = | calcium/calmodulin-dependent serine protein kinase |
| CAT3 | = | cationic amino acid transporter 3 |
| CAPZ | = | actin capping protein |
| CD2AP | = | CD2 associated protein |
| CG | = | collapsing glomerulopathy |
| cGMP | = | cyclic guanosine monophosphate |
| CIN85 | = | Cbl-interacting protein of 85 kDa |
| CNTF | = | ciliary neurotrophic factor |
| COL4A3, COL4A4 | = | gene for α 3, α 4 chain of collagen IV |
| Cx43 | = | connexin 43 |
| DMS | = | diffuse mesangial sclerosis |
| DN | = | diabetic nephropathy |
| EAAT2 | = | excitator amino acid transporter 2 |
| ERM | = | ezrin, radixin, moesin |
| ESRF | = | end-stage renal failure |
| FAK | = | focal adhesion kinase |
| FP | = | foot process |
| FSGS | = | focal segmental glomerulosclerosis |
| GCW | = | glomerular capillary wall |
| GLEPP-1 | = | glomerular epithelial protein |
| GBM | = | glomerular basement membrane |
| GTP | = | guanosine triphosphate |
| HIF-1 | = | hypoxia inducible factor |
| HIV | = | human immunodeficiency virus |
| HIVAN | = | HIV-associated nephropathy |
| HN | = | Heymann nephritis, rat model of human membranous nephropathy |
| hsp | = | heat shock protein |
| IgAN | = | IgA nephropathy |
| IL | = | interleukin |
| ILK | = | integrin-linked kinase |
| IQGAP1 | = | IQ motif-containing GTPase activating protein 1 |
| JAM4 | = | junctional adhesion module 4 |
| LDL | = | low-density lipoprotein |
| LM | = | laminin |
| LMX1B | = | a member of the LIM homeodomain family of transcription factors |
| LN | = | lupus nephritis |
| LPS | = | lipopolysaccharide |
| MAGI2 | = | membrane-associated guanylate cyclase inverted 2 |
| MAGI-1 | = | MAGUK with inverted domain structure-1, a membrane-associated protein with one guanylate kinase, six PDZ, and two WW domains |
| MAGUK | = | membrane-associated guanylate cyclase kinase |
| MAP | = | microtubule associated proteins |
| MAPK | = | mitogen-activated protein kinase |
| MCD | = | minimal change disease |
| MCP-1 | = | monocyte chemoattractant protein-1 |
| MN | = | membranous nephropathy |
| MPZ | = | myelin protein 0, P0 |
| mTOR | = | mammalian Target of Rapamycin, a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription |
| MT1-MMP | = | membrane-type 1 matrix metalloproteinase |
| NADPH | = | nicotinamide adenine dinucleotide phosphate |
| NC1 domain | = | non-collagenous 1 domain |
| NF-κ B | = | nuclear factor kappa B |
| NHERF-2 | = | Na+/H+-exchanger regulatory factor 2 |
| NPHS1 | = | gene encoding nephrin |
| NPHS2 | = | gene encoding podocin |
| NS | = | nephrotic syndrome |
| ORG | = | obesity-related glomerulopathy |
| PA | = | puromycin aminonucleoside |
| PAN | = | puromycin aminonucleoside nephrosis |
| PECAM | = | platelet endothelial cell adhesion molecule |
| PDZ | = | postsynaptic density-95/discs large/zonula occludens-1-adapter domain |
| PF | = | permeability factor |
| PGE2 | = | prostaglandin E2 |
| PI3K | = | phosphoinositide 3-kinase |
| PIP | = | PINCH-1, ILK, α -parvin complex |
| PLCε1 | = | phospholipase C ε1 |
| PLCE1 | = | gene for PLCε1 |
| PPAR | = | peroxisome proliferator-activated receptors |
| PTPRO | = | receptor type protein tyrosine phosphatase |
| RANTES | = | regulated upon activation, normal T cells expressed and secreted |
| ROCK | = | Rho-associated protein kinase |
| ROS | = | reactive oxygen species |
| SD | = | slit diaphragm |
| Sgk1 | = | serum and glucocorticoids-related kinase |
| SV2B | = | synaptic vesicle protein 2B |
| TGFβ | = | transforming growth factor β |
| TNFα | = | tumor necrosis factor α |
| TRPC6 | = | transient receptor potential channel 6 |
| USF-1 | = | upstream stimulatory factor-1 |
| VEGF | = | vascular endothelial growth factor |
| WASP | = | Wiscott-Aldrich syndrome protein |
| WT1 | = | Wilms tumor 1, transcription factor mutated in patients with Wilms tumor |
| ZHX | = | zinc fingers and homeoboxes family of proteins |
| ZO-1 | = | zonula occludens-1 |
| Abbreviations | ||
| ACE | = | angiotensin converting enzyme |
| ACEI | = | angiotensin converting enzyme inhibitors |
| AGEs | = | advanced glycation end-products |
| Akt | = | serine-threonine-specific protein kinase, member of serine/threonine-specific protein kinase family, protein kinase B |
| ANP | = | atrial natriuretic peptide |
| AP-1 | = | activation protein-1 |
| Arp2/3 | = | actin-related proteins |
| ATP | = | adenosine triphosphate |
| AIIA | = | angiotensin II antagonists |
| bHLH | = | basic helix-loop-helix transcription factor |
| cAMP | = | cyclic adenosine monophosphate |
| CASK | = | calcium/calmodulin-dependent serine protein kinase |
| CAT3 | = | cationic amino acid transporter 3 |
| CAPZ | = | actin capping protein |
| CD2AP | = | CD2 associated protein |
| CG | = | collapsing glomerulopathy |
| cGMP | = | cyclic guanosine monophosphate |
| CIN85 | = | Cbl-interacting protein of 85 kDa |
| CNTF | = | ciliary neurotrophic factor |
| COL4A3, COL4A4 | = | gene for α 3, α 4 chain of collagen IV |
| Cx43 | = | connexin 43 |
| DMS | = | diffuse mesangial sclerosis |
| DN | = | diabetic nephropathy |
| EAAT2 | = | excitator amino acid transporter 2 |
| ERM | = | ezrin, radixin, moesin |
| ESRF | = | end-stage renal failure |
| FAK | = | focal adhesion kinase |
| FP | = | foot process |
| FSGS | = | focal segmental glomerulosclerosis |
| GCW | = | glomerular capillary wall |
| GLEPP-1 | = | glomerular epithelial protein |
| GBM | = | glomerular basement membrane |
| GTP | = | guanosine triphosphate |
| HIF-1 | = | hypoxia inducible factor |
| HIV | = | human immunodeficiency virus |
| HIVAN | = | HIV-associated nephropathy |
| HN | = | Heymann nephritis, rat model of human membranous nephropathy |
| hsp | = | heat shock protein |
| IgAN | = | IgA nephropathy |
| IL | = | interleukin |
| ILK | = | integrin-linked kinase |
| IQGAP1 | = | IQ motif-containing GTPase activating protein 1 |
| JAM4 | = | junctional adhesion module 4 |
| LDL | = | low-density lipoprotein |
| LM | = | laminin |
| LMX1B | = | a member of the LIM homeodomain family of transcription factors |
| LN | = | lupus nephritis |
| LPS | = | lipopolysaccharide |
| MAGI2 | = | membrane-associated guanylate cyclase inverted 2 |
| MAGI-1 | = | MAGUK with inverted domain structure-1, a membrane-associated protein with one guanylate kinase, six PDZ, and two WW domains |
| MAGUK | = | membrane-associated guanylate cyclase kinase |
| MAP | = | microtubule associated proteins |
| MAPK | = | mitogen-activated protein kinase |
| MCD | = | minimal change disease |
| MCP-1 | = | monocyte chemoattractant protein-1 |
| MN | = | membranous nephropathy |
| MPZ | = | myelin protein 0, P0 |
| mTOR | = | mammalian Target of Rapamycin, a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription |
| MT1-MMP | = | membrane-type 1 matrix metalloproteinase |
| NADPH | = | nicotinamide adenine dinucleotide phosphate |
| NC1 domain | = | non-collagenous 1 domain |
| NF-κ B | = | nuclear factor kappa B |
| NHERF-2 | = | Na+/H+-exchanger regulatory factor 2 |
| NPHS1 | = | gene encoding nephrin |
| NPHS2 | = | gene encoding podocin |
| NS | = | nephrotic syndrome |
| ORG | = | obesity-related glomerulopathy |
| PA | = | puromycin aminonucleoside |
| PAN | = | puromycin aminonucleoside nephrosis |
| PECAM | = | platelet endothelial cell adhesion molecule |
| PDZ | = | postsynaptic density-95/discs large/zonula occludens-1-adapter domain |
| PF | = | permeability factor |
| PGE2 | = | prostaglandin E2 |
| PI3K | = | phosphoinositide 3-kinase |
| PIP | = | PINCH-1, ILK, α -parvin complex |
| PLCε1 | = | phospholipase C ε1 |
| PLCE1 | = | gene for PLCε1 |
| PPAR | = | peroxisome proliferator-activated receptors |
| PTPRO | = | receptor type protein tyrosine phosphatase |
| RANTES | = | regulated upon activation, normal T cells expressed and secreted |
| ROCK | = | Rho-associated protein kinase |
| ROS | = | reactive oxygen species |
| SD | = | slit diaphragm |
| Sgk1 | = | serum and glucocorticoids-related kinase |
| SV2B | = | synaptic vesicle protein 2B |
| TGFβ | = | transforming growth factor β |
| TNFα | = | tumor necrosis factor α |
| TRPC6 | = | transient receptor potential channel 6 |
| USF-1 | = | upstream stimulatory factor-1 |
| VEGF | = | vascular endothelial growth factor |
| WASP | = | Wiscott-Aldrich syndrome protein |
| WT1 | = | Wilms tumor 1, transcription factor mutated in patients with Wilms tumor |
| ZHX | = | zinc fingers and homeoboxes family of proteins |
| ZO-1 | = | zonula occludens-1 |