Primary focal segmental glomerulosclerosis (FSGS) (WP3233)

Bos taurus

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.

Authors

Martina Summer-Kutmon , Alex Pico , Eric Weitz , and Lars Willighagen

Activity

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Organisms

Bos taurus

Communities

Renal Genomics Pathways

Annotations

Pathway Ontology

kidney failure pathway kidney failure pathway

Cell Type Ontology

glomerular capillary endothelial cell

Participants

Label Type Compact URI Comment
CsA Metabolite pubchem.compound:5284373
RITUXIMAB Metabolite cas:174722-31-7
MYCOPHENOLATE MOFETIL Metabolite pubchem.compound:5281078
ITGAV GeneProduct ensembl:ENSBTAG00000019929 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138448
TLR4 GeneProduct ensembl:ENSBTAG00000006240 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000136869
CAMK2B GeneProduct ensembl:ENSBTAG00000012653 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000058404
AKT1 GeneProduct ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000142208
DNM1 GeneProduct ensembl:ENSBTAG00000011307 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000106976
KIRREL3 GeneProduct ensembl:ENSBTAG00000006804 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000149571
INTB3 GeneProduct ensembl:ENSBTAG00000009987 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000259207
VCL GeneProduct ensembl:ENSBTAG00000021879 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000035403
JAG1 GeneProduct ensembl:ENSBTAG00000012817 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000101384
KIRREL2 GeneProduct ensembl:ENSBTAG00000007826 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000126259
NCK1 GeneProduct ensembl:ENSBTAG00000018427 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000158092
CD151 GeneProduct ensembl:ENSBTAG00000019569 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000177697
CTSL1 GeneProduct ensembl:ENSBTAG00000000720 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000135047
PTPRO GeneProduct ensembl:ENSBTAG00000006256 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000151490
LAMA5 GeneProduct ensembl:ENSBTAG00000003061 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000130702
DKK1 GeneProduct ensembl:ENSBTAG00000014218 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000107984
FYN GeneProduct ensembl:ENSBTAG00000011851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000010810
PLAUR GeneProduct ensembl:ENSBTAG00000013125 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000011422
PTK2 GeneProduct ensembl:ENSBTAG00000009578 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169398
IRF6 GeneProduct ensembl:ENSBTAG00000002849 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000117595
VTN GeneProduct ensembl:ENSBTAG00000016151 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000109072
YWHAQ GeneProduct ensembl:ENSBTAG00000002108 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000134308
SYNPO GeneProduct ensembl:ENSBTAG00000013744 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171992
TGFB1 GeneProduct ensembl:ENSBTAG00000020457 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105329
AGRN GeneProduct ensembl:ENSBTAG00000013191 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000188157
CD2AP GeneProduct ensembl:ENSBTAG00000000322 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000198087
KRT8 GeneProduct ensembl:ENSBTAG00000047000 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170421
NPHS2 GeneProduct ensembl:ENSBTAG00000002167 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000116218
LAMC1 GeneProduct ensembl:ENSBTAG00000022635 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000172037
NPHS1 GeneProduct ensembl:ENSBTAG00000007821 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000161270
PLCG1 GeneProduct ensembl:ENSBTAG00000017584 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000124181
CDKN1B GeneProduct ensembl:ENSBTAG00000018254 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000111276
PAX2 GeneProduct ensembl:ENSBTAG00000021566 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000075891
PODXL GeneProduct ensembl:ENSBTAG00000010452 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000128567
LMX1B GeneProduct ensembl:ENSBTAG00000010228 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000136944
MYO1E GeneProduct ensembl:ENSBTAG00000021538 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000157483
SCARB2 GeneProduct ensembl:ENSBTAG00000010956 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138760
FAT1 GeneProduct ensembl:ENSBTAG00000020657 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000083857
ITGB4 GeneProduct ensembl:ENSBTAG00000018169 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000132470
COL4A5 GeneProduct ensembl:ENSBTAG00000014575 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000188153
CDKN1C GeneProduct ensembl:ENSBTAG00000031184 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000129757
MME GeneProduct ensembl:ENSBTAG00000002075 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000196549
VIM GeneProduct ensembl:ENSBTAG00000018463 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000026025
CDKN1A GeneProduct ensembl:ENSBTAG00000008353 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000124762
PLCE1 GeneProduct ensembl:ENSBTAG00000018966 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138193
ACTN4 GeneProduct ensembl:ENSBTAG00000011215 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000130402
MYH9 GeneProduct ensembl:ENSBTAG00000010402 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000100345
SMARCAL1 GeneProduct ensembl:ENSBTAG00000003843 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138375
WT1 GeneProduct ensembl:ENSBTAG00000047268 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000184937
INF2 GeneProduct ensembl:ENSBTAG00000007187 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000203485
TRPC6 GeneProduct ensembl:ENSBTAG00000011227 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000137672
ACTN4 GeneProduct ensembl:ENSBTAG00000011215 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000130402
PCNA GeneProduct ensembl:ENSBTAG00000006065 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000132646
MKI67 GeneProduct ensembl:ENSBTAG00000002444 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000148773
CDH2 GeneProduct ensembl:ENSBTAG00000021190 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170558
CLDN1 GeneProduct ensembl:ENSBTAG00000013148 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000163347
COL4A3 GeneProduct ensembl:ENSBTAG00000021316 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169031
COL4A4 GeneProduct ensembl:ENSBTAG00000021310 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000081052
MGC142792 GeneProduct ensembl:ENSBTAG00000010971 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169756
CD80 GeneProduct ensembl:ENSBTAG00000018059 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000121594
NOTCH1 GeneProduct ensembl:ENSBTAG00000022799 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000148400
CTNNB1 GeneProduct ensembl:ENSBTAG00000016420 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000168036
LRP6 GeneProduct ensembl:ENSBTAG00000011761 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000070018
LRP5 GeneProduct ensembl:ENSBTAG00000005903 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000162337
TLN1 GeneProduct ensembl:ENSBTAG00000025868 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000137076
ILK GeneProduct ensembl:ENSBTAG00000000696 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000166333
ITGB1 GeneProduct ensembl:ENSBTAG00000015910 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000150093
ITGA3 GeneProduct ensembl:ENSBTAG00000019498 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000005884
DAG1 GeneProduct ensembl:ENSBTAG00000011580 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000173402
PARVA GeneProduct ensembl:ENSBTAG00000000700 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000197702
UTRN GeneProduct ensembl:ENSBTAG00000009665 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000152818
WNT1 GeneProduct ensembl:ENSBTAG00000015364 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000125084

References

  1. Mechanism of podocyte detachment: Targeting transmembrane molecules between podocytes and glomerular basement membrane. Hu G, Jiao B. Biomedicine & Aging Pathology [Internet]. 2013 Jan;3(1):36–42. Available from: http://dx.doi.org/10.1016/j.biomag.2013.01.007 DOI Scholia
  2. Toward the development of podocyte-specific drugs. Reiser J, Gupta V, Kistler AD. Kidney Int. 2010 Apr;77(8):662–8. PubMed Europe PMC Scholia
  3. Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients. Canaud G, Martinez F, Noël LH, Mamzer MF, Niaudet P, Legendre C. Transplant Rev (Orlando). 2010 Jul;24(3):121–8. PubMed Europe PMC Scholia
  4. Problems with “focal segmental glomerulosclerosis.” Howie AJ. Pediatr Nephrol. 2011 Aug;26(8):1197–205. PubMed Europe PMC Scholia
  5. Focal and segmental glomerulosclerosis: multiple pathways are involved. Meyrier A. Semin Nephrol. 2011 Jul;31(4):326–32. PubMed Europe PMC Scholia
  6. Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Rood IM, Deegens JKJ, Wetzels JFM. Nephrol Dial Transplant. 2012 Mar;27(3):882–90. PubMed Europe PMC Scholia
  7. Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis. Kato H, Susztak K. Semin Nephrol. 2012 Jul;32(4):350–6. PubMed Europe PMC Scholia
  8. Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, et al. Nat Med. 2013 Apr;19(4):481–7. PubMed Europe PMC Scholia