Primary Focal Segmental Glomerulosclerosis FSGS (Bos taurus)

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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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2572(79947) with a 97.0% conversion rate.

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Bibliography

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  1. Howie AJ; ''Problems with 'focal segmental glomerulosclerosis'.''; Pediatr Nephrol, 2011 PubMed
  2. Kato H, Susztak K; ''Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis.''; Semin Nephrol, 2012 PubMed
  3. Rood IM, Deegens JK, Wetzels JF; ''Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice.''; Nephrol Dial Transplant, 2012 PubMed
  4. Meyrier A; ''Focal and segmental glomerulosclerosis: multiple pathways are involved.''; Semin Nephrol, 2011 PubMed
  5. Reiser J, Gupta V, Kistler AD; ''Toward the development of podocyte-specific drugs.''; Kidney Int, 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. 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

History

CompareRevisionActionTimeUserComment
90024view19:32, 8 October 2016AlexanderPicoModified description
89877view12:53, 6 October 2016MkutmonOntology Term : 'renal failure pathway' added !
89875view12:52, 6 October 2016MkutmonModified description
80848view15:28, 30 June 2015MkutmonNew pathway

External references

Datanodes

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NameTypeDatabase referenceComment
ACTN4GeneProductENSBTAG00000011215 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000130402
AGRNGeneProductENSBTAG00000013191 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000188157
AKT1GeneProductENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000142208
CAMK2BGeneProductENSBTAG00000012653 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000058404
CD151GeneProductENSBTAG00000019569 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000177697
CD2APGeneProductENSBTAG00000000322 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000198087
CD80GeneProductENSBTAG00000018059 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000121594
CDH2GeneProductENSBTAG00000021190 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170558
CDKN1AGeneProductENSBTAG00000008353 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000124762
CDKN1BGeneProductENSBTAG00000018254 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000111276
CDKN1CGeneProductENSBTAG00000031184 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000129757
CLDN1GeneProductENSBTAG00000013148 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000163347
COL4A3GeneProductENSBTAG00000021316 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169031
COL4A4GeneProductENSBTAG00000021310 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000081052
COL4A5GeneProductENSBTAG00000014575 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000188153
CR1GeneProduct
CTNNB1GeneProductENSBTAG00000016420 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000168036
CTSL1GeneProductENSBTAG00000000720 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000135047
CsAMetabolite5284373 (PubChem-compound)
DAG1GeneProductENSBTAG00000011580 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000173402
DKK1GeneProductENSBTAG00000014218 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000107984
DNM1GeneProductENSBTAG00000011307 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000106976
FAT1GeneProductENSBTAG00000020657 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000083857
FYNGeneProductENSBTAG00000011851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000010810
ILKGeneProductENSBTAG00000000696 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000166333
INF2GeneProductENSBTAG00000007187 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000203485
INTB3GeneProductENSBTAG00000009987 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000259207
IRF6GeneProductENSBTAG00000002849 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000117595
ITGA3GeneProductENSBTAG00000019498 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000005884
ITGAVGeneProductENSBTAG00000019929 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138448
ITGB1GeneProductENSBTAG00000015910 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000150093
ITGB4GeneProductENSBTAG00000018169 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000132470
JAG1GeneProductENSBTAG00000012817 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000101384
KIRREL2GeneProductENSBTAG00000007826 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000126259
KIRREL3GeneProductENSBTAG00000006804 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000149571
KRT8GeneProductENSBTAG00000047000 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170421
LAMA5GeneProductENSBTAG00000003061 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000130702
LAMC1GeneProductENSBTAG00000022635 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000172037
LMX1BGeneProductENSBTAG00000010228 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000136944
LRP5GeneProductENSBTAG00000005903 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000162337
LRP6GeneProductENSBTAG00000011761 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000070018
MGC142792GeneProductENSBTAG00000010971 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169756
MKI67GeneProductENSBTAG00000002444 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000148773
MMEGeneProductENSBTAG00000002075 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000196549
MT-TL1GeneProduct
MYCOPHENOLATE MOFETILMetabolite5281078 (PubChem-compound)
MYH9GeneProductENSBTAG00000010402 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000100345
MYO1EGeneProductENSBTAG00000021538 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000157483
NCK1GeneProductENSBTAG00000018427 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000158092
NOTCH1GeneProductENSBTAG00000022799 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000148400
NPHS1GeneProductENSBTAG00000007821 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000161270
NPHS2GeneProductENSBTAG00000002167 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000116218
PARVAGeneProductENSBTAG00000000700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000197702
PAX2GeneProductENSBTAG00000021566 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000075891
PCNAGeneProductENSBTAG00000006065 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000132646
PLAURGeneProductENSBTAG00000013125 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000011422
PLCE1GeneProductENSBTAG00000018966 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138193
PLCG1GeneProductENSBTAG00000017584 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000124181
PODXLGeneProductENSBTAG00000010452 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000128567
PTK2GeneProductENSBTAG00000009578 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169398
PTPROGeneProductENSBTAG00000006256 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000151490
RITUXIMABMetabolite174722-31-7 (CAS)
SCARB2GeneProductENSBTAG00000010956 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138760
SMARCAL1GeneProductENSBTAG00000003843 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000138375
SYNPOGeneProductENSBTAG00000013744 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171992
TGFB1GeneProductENSBTAG00000020457 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105329
TLN1GeneProductENSBTAG00000025868 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000137076
TLR4GeneProductENSBTAG00000006240 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000136869
TRPC6GeneProductENSBTAG00000011227 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000137672
UTRNGeneProductENSBTAG00000009665 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000152818
VCLGeneProductENSBTAG00000021879 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000035403
VIMGeneProductENSBTAG00000018463 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000026025
VTNGeneProductENSBTAG00000016151 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000109072
WNT1GeneProductENSBTAG00000015364 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000125084
WT1GeneProductENSBTAG00000047268 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000184937
YWHAQGeneProductENSBTAG00000002108 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000134308

Annotated Interactions

No annotated interactions
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