Primary focal segmental glomerulosclerosis (FSGS) (WP2572)

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 [https://assays.cancer.gov/available_assays?wp_id=WP2572 CPTAC Assay Portal]
last edited

Authors

DMicael, MaintBot, Egonw, Mkutmon, Zari, AlexanderPico, AMTan, Khanspers, Eweitz, and Finterly

Cited In

Organism

Homo sapiens

Communities

Renal Genomics Pathways

Annotations

Cell Type Ontology: glomerular capillary endothelial cell

Disease Ontology: focal segmental glomerulosclerosis

Pathway Ontology: kidney failure pathway

Participants

Label Type Compact Identifier
ITGAV GeneProduct ensembl:ENSG00000138448
TLR4 GeneProduct ensembl:ENSG00000136869
CAMK2B GeneProduct ensembl:ENSG00000058404
AKT1 GeneProduct ensembl:ENSG00000142208
DNM1 GeneProduct ensembl:ENSG00000106976
KIRREL3 GeneProduct ensembl:ENSG00000149571
ITGB3 GeneProduct ensembl:ENSG00000259207
VCL GeneProduct ensembl:ENSG00000035403
JAG1 GeneProduct ensembl:ENSG00000101384
KIRREL2 GeneProduct ensembl:ENSG00000126259
NCK1 GeneProduct ensembl:ENSG00000158092
CD151 GeneProduct ensembl:ENSG00000177697
CTSL GeneProduct ensembl:ENSG00000135047
PTPRO GeneProduct ensembl:ENSG00000151490
LAMA5 GeneProduct ensembl:ENSG00000130702
DKK1 GeneProduct ensembl:ENSG00000107984
FYN GeneProduct ensembl:ENSG00000010810
PLAUR GeneProduct ensembl:ENSG00000011422
FAK GeneProduct ensembl:ENSG00000169398
IRF6 GeneProduct ensembl:ENSG00000117595
VTN GeneProduct ensembl:ENSG00000109072
14-3-3 GeneProduct ensembl:ENSG00000134308
SYNPO GeneProduct ensembl:ENSG00000171992
TGFB1 GeneProduct ensembl:ENSG00000105329
AGRN GeneProduct ensembl:ENSG00000188157
CD2AP GeneProduct ensembl:ENSG00000198087
CsA Metabolite pubchem.compound:5284373
KRT8 GeneProduct ensembl:ENSG00000170421
NPHS2 GeneProduct ensembl:ENSG00000116218
LAMB2 GeneProduct ensembl:ENSG00000172037
NPHS1 GeneProduct ensembl:ENSG00000161270
PLCG1 GeneProduct ensembl:ENSG00000124181
CDKN1B GeneProduct ensembl:ENSG00000111276
RITUXIMAB Metabolite cas:174722-31-7
CR1 GeneProduct ensembl:ENSG00000203710
PAX2 GeneProduct ensembl:ENSG00000075891
PODXL GeneProduct ensembl:ENSG00000128567
LMX1B GeneProduct ensembl:ENSG00000136944
MYO1E GeneProduct ensembl:ENSG00000157483
SCARB2 GeneProduct ensembl:ENSG00000138760
MT-TL1 GeneProduct ensembl:ENSG00000209082
NON-MUSCLE MYOSIN-1E GeneProduct ensembl:ENSG00000157483
FAT1 GeneProduct ensembl:ENSG00000083857
LMX1B GeneProduct ensembl:ENSG00000136944
ITGB4 GeneProduct ensembl:ENSG00000132470
MT-TL1 GeneProduct ensembl:ENSG00000209082
COL4A5 GeneProduct ensembl:ENSG00000188153
CDKN1C GeneProduct ensembl:ENSG00000129757
MME GeneProduct ensembl:ENSG00000196549
MYCOPHENOLATE MOFETIL Metabolite pubchem.compound:5281078
VIM GeneProduct ensembl:ENSG00000026025
CDKN1A GeneProduct ensembl:ENSG00000124762
CD151 GeneProduct ensembl:ENSG00000177697
PODXL GeneProduct ensembl:ENSG00000128567
NPHS1 GeneProduct ensembl:ENSG00000161270
PLCE1 GeneProduct ensembl:ENSG00000138193
CD2AP GeneProduct ensembl:ENSG00000198087
ACTN4 GeneProduct ensembl:ENSG00000130402
NMMHC GeneProduct ensembl:ENSG00000100345
HHARP GeneProduct ensembl:ENSG00000138375
WT1 GeneProduct ensembl:ENSG00000184937
FORMIN INF2 GeneProduct ensembl:ENSG00000203485
TRPC6 GeneProduct ensembl:ENSG00000137672
AACTININ4 GeneProduct ensembl:ENSG00000130402
CD2AP GeneProduct ensembl:ENSG00000198087
PHOSPHOLIPASE CE1 GeneProduct ensembl:ENSG00000138193
PODOCIN GeneProduct ensembl:ENSG00000116218
NEPHRIN GeneProduct ensembl:ENSG00000161270
MYH9 GeneProduct ensembl:ENSG00000100345
SMARCAL1 GeneProduct ensembl:ENSG00000138375
WT1 GeneProduct ensembl:ENSG00000184937
INF2 GeneProduct ensembl:ENSG00000203485
TRPC6 GeneProduct ensembl:ENSG00000137672
LAMB2 GeneProduct ensembl:ENSG00000172037
ITGB4 GeneProduct ensembl:ENSG00000132470
CD151 GeneProduct ensembl:ENSG00000177697
SCARB2 GeneProduct ensembl:ENSG00000138760
WT1 GeneProduct ensembl:ENSG00000184937
PCNA GeneProduct ensembl:ENSG00000132646
MKI67 GeneProduct ensembl:ENSG00000148773
CADHERIN GeneProduct ensembl:ENSG00000170558
CLDN1 GeneProduct ensembl:ENSG00000163347
WT1 GeneProduct ensembl:ENSG00000184937
SYNPO GeneProduct ensembl:ENSG00000171992
COL4A3 GeneProduct ensembl:ENSG00000169031
COL4A4 GeneProduct ensembl:ENSG00000081052
ACTN4 GeneProduct ensembl:ENSG00000130402
LIMS1 GeneProduct ensembl:ENSG00000169756
NPHS1 GeneProduct ensembl:ENSG00000161270
PODOCIN GeneProduct ensembl:ENSG00000116218
CD80 GeneProduct ensembl:ENSG00000121594
NOTCH1 GeneProduct ensembl:ENSG00000148400
SYNPO GeneProduct ensembl:ENSG00000171992
CTNNB1 GeneProduct ensembl:ENSG00000168036
NOTCH1 GeneProduct ensembl:ENSG00000148400
LRP6 GeneProduct ensembl:ENSG00000070018
LRP5 GeneProduct ensembl:ENSG00000162337
TRPC6 GeneProduct ensembl:ENSG00000137672
TLN1 GeneProduct ensembl:ENSG00000137076
ILK GeneProduct ensembl:ENSG00000166333
ITGB1 GeneProduct ensembl:ENSG00000150093
ITGA3 GeneProduct ensembl:ENSG00000005884
DAG1 GeneProduct ensembl:ENSG00000173402
PARVA GeneProduct ensembl:ENSG00000197702
ILK GeneProduct ensembl:ENSG00000166333
UTRN GeneProduct ensembl:ENSG00000152818
WNT1 GeneProduct ensembl:ENSG00000125084

References

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  6. Kato H, Susztak K. Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis. Semin Nephrol. 2012 Jul;32(4):350–6. PubMed Europe PMC Scholia
  7. Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, et al. Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Nat Med. 2013 Apr;19(4):481–7. PubMed Europe PMC Scholia