Primary Focal Segmental Glomerulosclerosis FSGS (Homo sapiens)

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Syndromic LAMB2 LMX1B SCARB2 ITGB4 MT-TL1 CD151 MYH9 SMARCAL1 WT1 P + SLIT DIAPHRAGM DISRUPTION APOPTOSIS CALCIUM Legend TT: Therapeutic Target (increase) TT: Therapeutic Target (decrease) F-ACTIN ACTIN MICRORNA 193A PKA CALCINEURIN P13K ACTIN AD: Autosomal Dominant AR:Autosomal Recessive 3P21 PODOCYTOPENIA Podocyte-Associated Genetic Glomerular Diseases PROTEIN 17Q25 GENE AR STABILIZES PODOCYTE CYTOSKELETON MATERNAL 10Q23 PRIMARY INJURY ESRD AR AR NUCLEUS 11P15.5 Nonsyndromic PRIMARY FSGS AR 15Q21-Q22 9Q33.3 TYPE 4Q21.1 PTPRO LAMA5 AGRN SYNPO FAK VCL CD151 IRF6 TLR4 DNM1 VTN PLAUR JAG1 FYN NCK1 TGFB1 CTSL 14-3-3 AKT1 ITGAV CAMK2B DKK1 ITGB3 KIRREL3 KIRREL2 NPHS1 CD2AP CsA KRT8 NPHS2 NPHS1 PLCG1 CDKN1B RITUXIMAB CR1 PAX2 PODXL MYO1E MT-TL1 NON-MUSCLE MYOSIN-1E FAT1 LMX1B COL4A5 COL4A3 COL4A4 CDKN1C MME MYCOPHENOLATE MOFETIL VIM CDKN1A PODXL NPHS1 PLCE1 CD2AP ACTN4 NMMHC HHARP WT1 FORMIN INF2 TRPC6 AACTININ4 CD2AP PHOSPHOLIPASE CE1 PODOCIN NEPHRIN INF2 TRPC6 1Q25-Q31 19Q13 6P12.3 11P13 2Q35 19Q13.1 22Q12.3 11Q21-22 14Q CHROMOSOME TRANSMISSION AR AR AD AD/AR AD AD AD AR COMPLEX LAMB2 ITGB4 CD151 AR SCARB2 AR AD WT1 PCNA MKI67 CADHERIN CLDN1 DESTRUCTION OF PODOCYTE ARCHITECTURE NUCLEUS PODOCYTE TT WT1 SYNPO ACTN4 GLOMERULAR BASEMENT MEMBRANE NORMAL PODOCYTE LIMS1 PODOCIN CD80 NOTCH1 + P - SYNPO GLOMERULAR BASEMENT MEMBRANE TT TT TT TT TT TT TT TT TT TT TT TT TT CTNNB1 NOTCH1 LRP6 LRP5 TT TT TT TRPC6 TT TT TT TT TT TT TT TT TT TT TT GLOMERULAR BASEMENT MEMBRANE NORMAL EPITOPES PAX TT ANTICLA4 TT TLN1 ILK ITGB1 ITGA3 Proteins involved in Podocyte cytoskeleton DAG1 PARVA ILK UTRN WNT1 Y-SECRETASE Name: Primary Focal Segmental Glomerulosclerosis FSGS Organism: Homo sapiens


Description

Primary or idiopathic focal segmental glomerulosclerosis (FSGS) a cause of nephrotic syndrome in children and adolescents, as well as an important cause of end stage renal disease in adults. FSGS is mainly associated with foot process effacement, proliferation of mesangial, endothelial and epithelial cells in the early stages followed by collapse of glomerular capillaries leading to scarring. It may lead to dramatic manifestations such as proteinuria, hypoaluminemia, and hypertension. Also, there are many inheritable genetic abnormalities that can cause podocyte damage of FSGS caused by mutations in proteins that are important for podocyte function. The genes include CD2AP, MYO1E, WNT1, and LAMB2. On the far left, the diagram illustrates molecular interactions between a normal podocyte and matrix interactions. ACTN4 and SYNPO and DAG1 interacting with AGRN associate with the actin cytoskeleton; these actin associated proteins might play a role in maintaining podocyte and GBM architecture. DAG1 binds to UTRN, which in turn binds an actin filament, thus completing the link between the actin-based cytoskeleton and the extracellular matrix. Podocyte foot processes are anchored to the glomerular basement membrane (GBM) via ITGB1 and ITGA3 integrin complex and DAG1-UTRN complex. Transmembrane proteins such as LAMA5 and CD151 bind to ITGB1 and ITGA3, respectively. The intracellular integrins combine with cytoskeletal via intermediates which include TLN1, VCL, and PAX complex and the ILK, PARVA, and LIMS1 complex. (Guanghua Hu et. al 2013 - Biomedicine and Aging Pathology vol 3) Upon primary podocyte injury, there are multiple pathways involved in podocyte injury. "Sustaining NPHS1 and phosphorylation might contribute to both anti-apoptotic signaling and actin polymerization. The CD80 pathway may be targeted by TLR4 or blocking the binding of B7-1 to slit diaphragm structure proteins such as KIRREL2/3. PLAUR could be inhibited by interfering with binding of PLAUR and ITGAV/B3 integrin, inhibiting ITGB3 integrin activation, or inhibiting binding of ITGAV/B3 integrin to VTN. The notch pathway can be targeted by interfering with its upstream activation by blocking the TGF-β1 effect, inhibiting γ-secretase, which is required for proteolytic receptor activation, or interfering with target gene transcription." (Reiser J. et al 2010 - Kidney Int vol 77) Post podocyte development, increased activation of NOTCH1 and WNT/CTNNB1 activities contribute to glomerulosclerosis. Expression of JAG1 on the ligand-expressing cell induces proteolytic cleavage of the Notch receptor on the signal-receiving cell, releasing the NOTCH1. DKK1 inhibits WNT1 binding to LRP5/6. By inhibiting the destruction of CTNNB1, CTNNB1 is stablilized. "The CTSL pathway could be targeted by specifically inhibiting CTSL expression or activity, shifting the equilibrium of SYNPO toward the phosphorylated form by inhibiting calcineurin-mediated dephosphorylation or enhancing PKA or CAMK2B-mediated phosphorylation, protecting SYNPO and DNM1 by compounds that bind to the CTSL cleavage site, or delivering cleavage-resistant SYNPO and DNM1 mutants." (Reiser J. et al 2010 - Kidney Int vol 77) The destruction of podocyte's cytoskeleton architecture leads to lose of normal podocyte epitopes such as VIM, SYNPO, and WT1, and lose of cyclin-dependent kinase inhibitors CDKN1C and CDKN1B. Also, podocytes acquire proliferation of CDKN1A. This leads to podocytopenia which have been shown to cause primary FSGS and then followed by end-stage renal disease (ESRD). FSGS is also induced by microRNA-193a and its downregulation of WT1, destroying podocyte foot processes. There is insufficient evidence that segmental glomerular lesions can be caused by other drugs or toxins, apart from some used experimentally such as doxorubicin and puromycin aminonucleoside. Treatments such as steroids, high-dose cyclosporine, ritxuximab can reduce proteinuria based on their immunosuppressive properties and through stabilization of the podocyte actin cytoskeleton.

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Ontology Terms

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Bibliography

  1. Kato H, Susztak K; ''Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis.''; Semin Nephrol, 2012 PubMed
  2. Meyrier A; ''Focal and segmental glomerulosclerosis: multiple pathways are involved.''; Semin Nephrol, 2011 PubMed
  3. Reiser J, Gupta V, Kistler AD; ''Toward the development of podocyte-specific drugs.''; Kidney Int, 2010 PubMed
  4. Rood IM, Deegens JK, Wetzels JF; ''Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice.''; Nephrol Dial Transplant, 2012 PubMed
  5. Canaud G, Martinez F, Noط·آ£ط¢آ«l LH, Mamzer MF, Niaudet P, Legendre C; ''Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients.''; Transplant Rev (Orlando), 2010 PubMed
  6. Hu, G, Jiao,B; ''Mechanism of podocyte detachment: Targeting transmembrane molecules between podocytes and glomerular basement membrane''; Biomedicine & Aging Pathology, 2013
  7. Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, Tauber S, Bilban M, Wang S, Kain R, Bط·آ£ط¢آ¶hmig GA, Moeller MJ, Grط·آ£ط¢آ¶ne HJ, Englert C, Martinez J, Kerjaschki D; ''Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1.''; Nat Med, 2013 PubMed
  8. Howie AJ; ''Problems with 'focal segmental glomerulosclerosis'.''; Pediatr Nephrol, 2011 PubMed
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History

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RevisionActionTimeUserComment
97626view 01:58, 31 May 2018AMTanOntology Term : 'focal segmental glomerulosclerosis' added !
90019view 12:28, 8 October 2016AlexanderPicoModified description
89876view 05:52, 6 October 2016MkutmonModified description
79947view 03:16, 28 April 2015ZariChanged HNGC ID to Ensembl ID TGFB1
79296view 06:19, 20 March 2015Zari
79295view 05:20, 20 March 2015Zarichanged Identifier for VNT
78521view 03:29, 7 January 2015MaintBotadded missing graphIds
76327view 01:08, 2 July 2014MkutmonFixed identifier for FAK
76326view 01:07, 2 July 2014MkutmonChanged database annotations from "Ensembl Human" to "Ensembl"
76325view 01:03, 2 July 2014Mkutmonreplaced annotation for geneproducts from OMIM to Ensembl
76324view 01:02, 2 July 2014Mkutmonreplaced annotation for geneproducts from OMIM to Ensembl
72200view 04:10, 27 October 2013EgonwFixed the PubChem-compound database name.
71217view 13:30, 14 October 2013DMicaelSpecify description
71211view 11:08, 14 October 2013DMicaelSpecify description
71210view 11:06, 14 October 2013DMicaelSpecify description
71209view 11:04, 14 October 2013DMicaelSpecify description
71208view 11:01, 14 October 2013DMicaelSpecify description
71207view 10:56, 14 October 2013DMicaelSpecify description
71152view 14:17, 10 October 2013MaintBotfixed publication xrefs
71099view 10:04, 4 October 2013DMicaelModified title
71098view 10:02, 4 October 2013DMicaelModified description
71097view 09:34, 4 October 2013DMicaelModified description
71080view 19:24, 2 October 2013DMicaelModified title
71072view 20:18, 1 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71071view 20:14, 1 October 2013DMicaelOntology Term : 'renal failure pathway' added !
71065view 14:15, 1 October 2013DMicaelModified title
71064view 14:03, 1 October 2013DMicaelModified description
71063view 13:57, 1 October 2013DMicaelModified description
71062view 13:52, 1 October 2013DMicaelNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
14-3-3GeneProductENSG00000134308 (Ensembl)
AACTININ4GeneProductENSG00000130402 (Ensembl)
ACTN4GeneProductENSG00000130402 (Ensembl)
AGRNGeneProductENSG00000188157 (Ensembl)
AKT1GeneProductENSG00000142208 (Ensembl)
CADHERINGeneProductENSG00000170558 (Ensembl)
CAMK2BGeneProductENSG00000058404 (Ensembl)
CD151GeneProductENSG00000177697 (Ensembl)
CD2APGeneProductENSG00000198087 (Ensembl)
CD80GeneProductENSG00000121594 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl)
CDKN1BGeneProductENSG00000111276 (Ensembl)
CDKN1CGeneProductENSG00000129757 (Ensembl)
CLDN1GeneProductENSG00000163347 (Ensembl)
COL4A3GeneProductENSG00000169031 (Ensembl)
COL4A4GeneProductENSG00000081052 (Ensembl)
COL4A5GeneProductENSG00000188153 (Ensembl)
CR1GeneProductENSG00000203710 (Ensembl)
CTNNB1GeneProductENSG00000168036 (Ensembl)
CTSLGeneProductENSG00000135047 (Ensembl)
CsAMetabolite5284373 (PubChem-compound)
DAG1GeneProductENSG00000173402 (Ensembl)
DKK1GeneProductENSG00000107984 (Ensembl)
DNM1GeneProductENSG00000106976 (Ensembl)
FAKGeneProductENSG00000169398 (Ensembl)
FAT1GeneProductENSG00000083857 (Ensembl)
FORMIN INF2 GeneProductENSG00000203485 (Ensembl)
FYNGeneProductENSG00000010810 (Ensembl)
HHARPGeneProductENSG00000138375 (Ensembl)
ILKGeneProductENSG00000166333 (Ensembl)
INF2GeneProductENSG00000203485 (Ensembl)
IRF6GeneProductENSG00000117595 (Ensembl)
ITGA3GeneProductENSG00000005884 (Ensembl)
ITGAVGeneProductENSG00000138448 (Ensembl)
ITGB1GeneProductENSG00000150093 (Ensembl)
ITGB3GeneProductENSG00000259207 (Ensembl)
ITGB4GeneProductENSG00000132470 (Ensembl)
JAG1GeneProductENSG00000101384 (Ensembl)
KIRREL2GeneProductENSG00000126259 (Ensembl)
KIRREL3GeneProductENSG00000149571 (Ensembl)
KRT8GeneProductENSG00000170421 (Ensembl)
LAMA5GeneProductENSG00000130702 (Ensembl)
LAMB2GeneProductENSG00000172037 (Ensembl)
LIMS1GeneProductENSG00000169756 (Ensembl)
LMX1BGeneProductENSG00000136944 (Ensembl)
LRP5GeneProductENSG00000162337 (Ensembl)
LRP6GeneProductENSG00000070018 (Ensembl)
MKI67GeneProductENSG00000148773 (Ensembl)
MMEGeneProductENSG00000196549 (Ensembl)
MT-TL1GeneProductENSG00000209082 (Ensembl)
MYCOPHENOLATE MOFETILMetabolite5281078 (PubChem-compound)
MYH9GeneProductENSG00000100345 (Ensembl)
MYO1EGeneProductENSG00000157483 (Ensembl)
NCK1GeneProductENSG00000158092 (Ensembl)
NEPHRIN GeneProductENSG00000161270 (Ensembl)
NMMHCGeneProductENSG00000100345 (Ensembl)
NON-MUSCLE MYOSIN-1EGeneProductENSG00000157483 (Ensembl)
NOTCH1GeneProductENSG00000148400 (Ensembl)
NPHS1GeneProductENSG00000161270 (Ensembl)
NPHS2GeneProductENSG00000116218 (Ensembl)
PARVAGeneProductENSG00000197702 (Ensembl)
PAX2GeneProductENSG00000075891 (Ensembl)
PCNAGeneProductENSG00000132646 (Ensembl)
PHOSPHOLIPASE CE1GeneProductENSG00000138193 (Ensembl)
PLAURGeneProductENSG00000011422 (Ensembl)
PLCE1GeneProductENSG00000138193 (Ensembl)
PLCG1GeneProductENSG00000124181 (Ensembl)
PODOCINGeneProductENSG00000116218 (Ensembl)
PODXLGeneProductENSG00000128567 (Ensembl)
PTPROGeneProductENSG00000151490 (Ensembl)
RITUXIMABMetabolite174722-31-7 (CAS)
SCARB2GeneProductENSG00000138760 (Ensembl)
SMARCAL1GeneProductENSG00000138375 (Ensembl)
SYNPOGeneProductENSG00000171992 (Ensembl)
TGFB1GeneProductENSG00000105329 (Ensembl)
TLN1GeneProductENSG00000137076 (Ensembl)
TLR4GeneProductENSG00000136869 (Ensembl)
TRPC6GeneProductENSG00000137672 (Ensembl)
UTRNGeneProductENSG00000152818 (Ensembl)
VCLGeneProductENSG00000035403 (Ensembl)
VIMGeneProductENSG00000026025 (Ensembl)
VTNGeneProductENSG00000109072 (Ensembl)
WNT1GeneProductENSG00000125084 (Ensembl)
WT1GeneProductENSG00000184937 (Ensembl)

Annotated Interactions

<cite>No annotated interactions</cite>