Primary focal segmental glomerulosclerosis (FSGS) (WP2573)

Mus musculus

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

Deborah Micael , Egon Willighagen , Martina Summer-Kutmon , Max Van Son , Denise Slenter , Eric Weitz , and Lars Willighagen

Activity

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Organisms

Mus musculus

Communities

Renal Genomics Pathways

Annotations

Cell Type Ontology

glomerular capillary endothelial cell glomerular capillary endothelial cell glomerular capillary endothelial cell

Pathway Ontology

kidney failure pathway kidney failure pathway

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:ENSMUSG00000027087
Tlr4 GeneProduct ensembl:ENSMUSG00000039005
Camk2b GeneProduct ensembl:ENSMUSG00000057897
Akt1 GeneProduct ensembl:ENSMUSG00000001729
Dnm1 GeneProduct ensembl:ENSMUSG00000026825
Kirrel3 GeneProduct ensembl:ENSMUSG00000032036
Itgb3 GeneProduct ensembl:ENSMUSG00000020689
Vcl GeneProduct ensembl:ENSMUSG00000021823
Jag1 GeneProduct ensembl:ENSMUSG00000027276
Kirrel2 GeneProduct ensembl:ENSMUSG00000036915
Nck1 GeneProduct ensembl:ENSMUSG00000032475
Cd151 GeneProduct ensembl:ENSMUSG00000025510
Ctsl GeneProduct ensembl:ENSMUSG00000021477
Ptpro GeneProduct ensembl:ENSMUSG00000030223
Lama5 GeneProduct ensembl:ENSMUSG00000015647
Dkk1 GeneProduct ensembl:ENSMUSG00000024868
Fyn GeneProduct ensembl:ENSMUSG00000019843
Plaur GeneProduct ensembl:ENSMUSG00000046223
Ptk2 GeneProduct ensembl:ENSMUSG00000022607
Irf6 GeneProduct ensembl:ENSMUSG00000026638
Vtn GeneProduct ensembl:ENSMUSG00000017344
Ywhaq GeneProduct ensembl:ENSMUSG00000076432
Synpo GeneProduct ensembl:ENSMUSG00000043079
Tgfb1 GeneProduct ensembl:ENSMUSG00000002603
Agrn GeneProduct ensembl:ENSMUSG00000041936
Cd2ap GeneProduct ensembl:ENSMUSG00000061665
Krt8 GeneProduct ensembl:ENSMUSG00000049382
Nphs2 GeneProduct ensembl:ENSMUSG00000026602
Lamb2 GeneProduct ensembl:ENSMUSG00000052911
Nphs1 GeneProduct ensembl:ENSMUSG00000006649
Plcg1 GeneProduct ensembl:ENSMUSG00000016933
Cdkn1b GeneProduct ensembl:ENSMUSG00000003031
Cr1l GeneProduct ensembl:ENSMUSG00000016481
Pax2 GeneProduct ensembl:ENSMUSG00000004231
Podxl GeneProduct ensembl:ENSMUSG00000025608
Lmx1b GeneProduct ensembl:ENSMUSG00000038765
Myo1e GeneProduct ensembl:ENSMUSG00000032220
Scarb2 GeneProduct ensembl:ENSMUSG00000029426
MT-TL1 GeneProduct ncbigene:4567
Fat1 GeneProduct ensembl:ENSMUSG00000070047
Itgb4 GeneProduct ensembl:ENSMUSG00000020758
Col4a5 GeneProduct ensembl:ENSMUSG00000031274
Cdkn1c GeneProduct ensembl:ENSMUSG00000037664
Mme GeneProduct ensembl:ENSMUSG00000027820
Vim GeneProduct ensembl:ENSMUSG00000026728
Cdkn1a GeneProduct ensembl:ENSMUSG00000023067
Plce1 GeneProduct ensembl:ENSMUSG00000024998
ACTN4 GeneProduct ensembl:ENSMUSG00000054808
Myh9 GeneProduct ensembl:ENSMUSG00000022443
Smarcal1 GeneProduct ensembl:ENSMUSG00000039354
Wt1 GeneProduct ensembl:ENSMUSG00000016458
Inf2 GeneProduct ensembl:ENSMUSG00000037679
Trpc6 GeneProduct ensembl:ENSMUSG00000031997
Pcna GeneProduct ensembl:ENSMUSG00000027342
Mki67 GeneProduct ensembl:ENSMUSG00000031004
Cdh2 GeneProduct ensembl:ENSMUSG00000024304
Cldn1 GeneProduct ensembl:ENSMUSG00000022512
Col4a3 GeneProduct ensembl:ENSMUSG00000079465
Col4a4 GeneProduct ensembl:ENSMUSG00000067158
Lims1 GeneProduct ensembl:ENSMUSG00000019920
Cd80 GeneProduct ensembl:ENSMUSG00000075122
Notch1 GeneProduct ensembl:ENSMUSG00000026923
Ctnnb1 GeneProduct ensembl:ENSMUSG00000006932
Lrp6 GeneProduct ensembl:ENSMUSG00000030201
Lrp5 GeneProduct ensembl:ENSMUSG00000024913
Tln1 GeneProduct ensembl:ENSMUSG00000028465
Ilk GeneProduct ensembl:ENSMUSG00000030890
Itgb1 GeneProduct ensembl:ENSMUSG00000025809
Itga3 GeneProduct ensembl:ENSMUSG00000001507
Dag1 GeneProduct ensembl:ENSMUSG00000039952
PARVA GeneProduct ensembl:ENSMUSG00000030770
Utrn GeneProduct ensembl:ENSMUSG00000019820
WNT1 GeneProduct omim:164820

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. Focal and segmental glomerulosclerosis: multiple pathways are involved. Meyrier A. Semin Nephrol. 2011 Jul;31(4):326–32. PubMed Europe PMC Scholia
  5. 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
  6. Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis. Kato H, Susztak K. Semin Nephrol. 2012 Jul;32(4):350–6. PubMed Europe PMC Scholia
  7. 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