Primary Focal Segmental Glomerulosclerosis FSGS (Homo sapiens)

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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.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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  1. Meyrier A; ''Focal and segmental glomerulosclerosis: multiple pathways are involved.''; Semin Nephrol, 2011 PubMed Europe PMC Scholia
  2. Reiser J, Gupta V, Kistler AD; ''Toward the development of podocyte-specific drugs.''; Kidney Int, 2010 PubMed Europe PMC Scholia
  3. 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 Europe PMC Scholia
  4. 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 Europe PMC Scholia
  5. Howie AJ; ''Problems with 'focal segmental glomerulosclerosis'.''; Pediatr Nephrol, 2011 PubMed Europe PMC Scholia
  6. Kato H, Susztak K; ''Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis.''; Semin Nephrol, 2012 PubMed Europe PMC Scholia
  7. Hu, G, Jiao,B; ''Mechanism of podocyte detachment: Targeting transmembrane molecules between podocytes and glomerular basement membrane''; Biomedicine & Aging Pathology, 2013
  8. Rood IM, Deegens JK, Wetzels JF; ''Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice.''; Nephrol Dial Transplant, 2012 PubMed Europe PMC Scholia


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106533view23:58, 5 September 2019Khanspersfixed interactions
106532view23:51, 5 September 2019KhanspersModified description
105791view19:48, 15 August 2019KhanspersModified description
97626view08:58, 31 May 2018AMTanOntology Term : 'focal segmental glomerulosclerosis' added !
90019view19:28, 8 October 2016AlexanderPicoModified description
89876view12:52, 6 October 2016MkutmonModified description
79947view10:16, 28 April 2015ZariChanged HNGC ID to Ensembl ID TGFB1
79296view13:19, 20 March 2015Zari
79295view12:20, 20 March 2015Zarichanged Identifier for VNT
78521view10:29, 7 January 2015MaintBotadded missing graphIds
76327view08:08, 2 July 2014MkutmonFixed identifier for FAK
76326view08:07, 2 July 2014MkutmonChanged database annotations from "Ensembl Human" to "Ensembl"
76325view08:03, 2 July 2014Mkutmonreplaced annotation for geneproducts from OMIM to Ensembl
76324view08:02, 2 July 2014Mkutmonreplaced annotation for geneproducts from OMIM to Ensembl
72200view11:10, 27 October 2013EgonwFixed the PubChem-compound database name.
71217view20:30, 14 October 2013DMicaelSpecify description
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71152view21:17, 10 October 2013MaintBotfixed publication xrefs
71099view17:04, 4 October 2013DMicaelModified title
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71097view16:34, 4 October 2013DMicaelModified description
71080view02:24, 3 October 2013DMicaelModified title
71072view03:18, 2 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71071view03:14, 2 October 2013DMicaelOntology Term : 'renal failure pathway' added !
71065view21:15, 1 October 2013DMicaelModified title
71064view21:03, 1 October 2013DMicaelModified description
71063view20:57, 1 October 2013DMicaelModified description
71062view20:52, 1 October 2013DMicaelNew pathway

External references


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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

No annotated interactions

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