Primary Focal Segmental Glomerulosclerosis FSGS (Mus musculus)

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Syndromic Lamb2 Lmx1b Scarb2 Itgb4 MT-TL1 Cd151 Myh9 Smarcal1 Wt1 P CALCIUM ACTIN AR: Autosomal Dominant P13K TT: Therapeutic Target (decrease) APOPTOSIS CALCINEURIN ACTIN PKA AD: Autosomal Recessive + SLIT DIAPHRAGM DISRUPTION TT: Therapeutic Target (increase) Legend F-ACTIN MICRORNA 193A 3P21 PODOCYTOPENIA Podocyte-Associated Genetic Glomerular Diseases PROTEIN 17Q25 GENE AR STABILIZES PODOCYTE CYTOSKELETON MATERNAL 10Q23 PRIMARY INJURY ESRD AR AR NUCLEUS 11P15.5 Nonsyndromic PRIMARY FSGS AR 15Q21-Q22 9Q33.3 TYPE 4Q21.1 Itgav Tlr4 Camk2b Akt1 Dnm1 Itgb3 Vcl Jag1 Nck1 Cd151 Ctsl Ptpro Lama5 Dkk1 Fyn Plaur Ptk2 Irf6 Vtn Ywhaq Synpo Tgfb1 Agrn Kirrel3 Kirrel2 Nphs1 Cd2ap CsA Krt8 Nphs2 Nphs1 Plcg1 Cdkn1b RITUXIMAB Cr1l Pax2 Podxl Myo1e MT-TL1 Myo1e Fat1 Lmx1b Col4a5 Col4a3 Col4a4 Cdkn1c Mme MYCOPHENOLATE MOFETIL Vim Cdkn1a Podxl Nphs1 Plce1 Cd2ap ACTN4 Myh9 Smarcal1 Wt1 Inf2 Trpc6 ACTN4 Cd2ap Plce1 Nphs2 Nphs1 Inf2 Trpc6 1Q25-Q31 19Q13 6P12.3 11P13 2Q35 19Q13.1 22Q12.3 11Q21-22 14Q CHROMOSOME TRANSMISSION AR AR AD AD/AR AD AD AD AR COMPLEX Lamb2 Itgb4 Cd151 AR Scarb2 AR AD Wt1 Pcna Mki67 Cdh2 Cldn1 DESTRUCTION OF PODOCYTE ARCHITECTURE NUCLEUS PODOCYTE TT Wt1 Synpo ACTN4 GLOMERULAR BASEMENT MEMBRANE NORMAL PODOCYTE Lims1 Nphs2 Cd80 Notch1 + P - Synpo GLOMERULAR BASEMENT MEMBRANE TT TT TT TT TT TT TT TT TT TT TT TT TT Ctnnb1 Notch1 Lrp6 Lrp5 TT TT TT Trpc6 TT TT TT TT TT TT TT TT TT TT TT GLOMERULAR BASEMENT MEMBRANE NORMAL EPITOPES PAX TT ANTICLA4 TT Tln1 Ilk Itgb1 Itga3 Proteins involved in Podocyte cytoskeleton Dag1 PARVA Ilk Utrn WNT1 Y-SECRETASE Name: Primary Focal Segmental Glomerulosclerosis FSGS Organism: 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.

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  1. Canaud G, Martinez F, Noël LH, Mamzer MF, Niaudet P, Legendre C; ''Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients.''; Transplant Rev (Orlando), 2010 PubMed
  2. Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, Tauber S, Bilban M, Wang S, Kain R, Böhmig GA, Moeller MJ, Gröne HJ, Englert C, Martinez J, Kerjaschki D; ''Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1.''; Nat Med, 2013 PubMed
  3. Rood IM, Deegens JK, Wetzels JF; ''Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice.''; Nephrol Dial Transplant, 2012 PubMed
  4. Hu, G, Jiao,B; ''Mechanism of podocyte detachment: Targeting transmembrane molecules between podocytes and glomerular basement membrane''; Biomedicine & Aging Pathology, 2013
  5. Meyrier A; ''Focal and segmental glomerulosclerosis: multiple pathways are involved.''; Semin Nephrol, 2011 PubMed
  6. Kato H, Susztak K; ''Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis.''; Semin Nephrol, 2012 PubMed
  7. Reiser J, Gupta V, Kistler AD; ''Toward the development of podocyte-specific drugs.''; Kidney Int, 2010 PubMed
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97540view 07:33, 24 May 2018DeSlAnother Entrez to Entrez Gene
97537view 07:32, 24 May 2018DeSlChanged Database from Entrez to Entrez Gene.
97535view 07:30, 24 May 2018DeSlAACTININ4 should be ACTN4 (according to original OMIM ID). Added Ensembl ID for it now.
97533view 07:26, 24 May 2018DeSlChanged PARVA ID from OMIM to Ensembl
97531view 07:24, 24 May 2018DeSlChanged MT-TL1 ID from OMIM to Entrez
97529view 07:21, 24 May 2018DeSlChanged ID for ACTN4 from OMIM to ENSEMBL
97504view 06:29, 24 May 2018MaxvansonChanged some identifiers for better linking to other databases
89874view 05:51, 6 October 2016MkutmonModified description
79651view 04:44, 1 April 2015EgonwUpdated the Ensembl data source names.
78429view 03:26, 7 January 2015MaintBotadded missing graphIds
72201view 04:12, 27 October 2013EgonwFixed the PubChem-compound database name.
71216view 13:25, 14 October 2013DMicaelSpecify description
71215view 13:21, 14 October 2013DMicaelSpecify description
71206view 10:49, 14 October 2013DMicaelSpecify description
71151view 14:12, 10 October 2013MaintBotone more publication ref
71150view 14:11, 10 October 2013MaintBotfixed remaining publication refs
71149view 13:48, 10 October 2013MaintBotFixed publication
71101view 10:07, 4 October 2013DMicaelModified description
71100view 10:06, 4 October 2013DMicaelModified title
71086view 14:58, 3 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71085view 10:19, 3 October 2013DMicaelOntology Term : 'CL:1001005' removed !
71082view 19:31, 2 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71081view 19:29, 2 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71079view 19:00, 2 October 2013DMicaelModified title
71076view 10:10, 2 October 2013DMicaelOntology Term : 'renal failure pathway' added !
71075view 10:03, 2 October 2013DMicaelNew pathway

External references


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NameTypeDatabase referenceComment
ACTN4GeneProductENSMUSG00000054808 (Ensembl)
AgrnGeneProductENSMUSG00000041936 (Ensembl)
Akt1GeneProductENSMUSG00000001729 (Ensembl)
Camk2bGeneProductENSMUSG00000057897 (Ensembl)
Cd151GeneProductENSMUSG00000025510 (Ensembl)
Cd2apGeneProductENSMUSG00000061665 (Ensembl)
Cd80GeneProductENSMUSG00000075122 (Ensembl)
Cdh2GeneProductENSMUSG00000024304 (Ensembl)
Cdkn1aGeneProductENSMUSG00000023067 (Ensembl)
Cdkn1bGeneProductENSMUSG00000003031 (Ensembl)
Cdkn1cGeneProductENSMUSG00000037664 (Ensembl)
Cldn1GeneProductENSMUSG00000022512 (Ensembl)
Col4a3GeneProductENSMUSG00000079465 (Ensembl)
Col4a4GeneProductENSMUSG00000067158 (Ensembl)
Col4a5GeneProductENSMUSG00000031274 (Ensembl)
Cr1lGeneProductENSMUSG00000016481 (Ensembl)
CsAMetabolite5284373 (PubChem-compound)
Ctnnb1GeneProductENSMUSG00000006932 (Ensembl)
CtslGeneProductENSMUSG00000021477 (Ensembl)
Dag1GeneProductENSMUSG00000039952 (Ensembl)
Dkk1GeneProductENSMUSG00000024868 (Ensembl)
Dnm1GeneProductENSMUSG00000026825 (Ensembl)
Fat1GeneProductENSMUSG00000070047 (Ensembl)
FynGeneProductENSMUSG00000019843 (Ensembl)
IlkGeneProductENSMUSG00000030890 (Ensembl)
Inf2GeneProductENSMUSG00000037679 (Ensembl)
Irf6GeneProductENSMUSG00000026638 (Ensembl)
Itga3GeneProductENSMUSG00000001507 (Ensembl)
ItgavGeneProductENSMUSG00000027087 (Ensembl)
Itgb1GeneProductENSMUSG00000025809 (Ensembl)
Itgb3GeneProductENSMUSG00000020689 (Ensembl)
Itgb4GeneProductENSMUSG00000020758 (Ensembl)
Jag1GeneProductENSMUSG00000027276 (Ensembl)
Kirrel2GeneProductENSMUSG00000036915 (Ensembl)
Kirrel3GeneProductENSMUSG00000032036 (Ensembl)
Krt8GeneProductENSMUSG00000049382 (Ensembl)
Lama5GeneProductENSMUSG00000015647 (Ensembl)
Lamb2GeneProductENSMUSG00000052911 (Ensembl)
Lims1GeneProductENSMUSG00000019920 (Ensembl)
Lmx1bGeneProductENSMUSG00000038765 (Ensembl)
Lrp5GeneProductENSMUSG00000024913 (Ensembl)
Lrp6GeneProductENSMUSG00000030201 (Ensembl)
MT-TL1GeneProduct4567 (Entrez Gene)
MYCOPHENOLATE MOFETILMetabolite5281078 (PubChem-compound)
Mki67GeneProductENSMUSG00000031004 (Ensembl)
MmeGeneProductENSMUSG00000027820 (Ensembl)
Myh9GeneProductENSMUSG00000022443 (Ensembl)
Myo1eGeneProductENSMUSG00000032220 (Ensembl)
Nck1GeneProductENSMUSG00000032475 (Ensembl)
Notch1GeneProductENSMUSG00000026923 (Ensembl)
Nphs1GeneProductENSMUSG00000006649 (Ensembl)
Nphs2GeneProductENSMUSG00000026602 (Ensembl)
PARVAGeneProductENSMUSG00000030770 (Ensembl)
Pax2GeneProductENSMUSG00000004231 (Ensembl)
PcnaGeneProductENSMUSG00000027342 (Ensembl)
PlaurGeneProductENSMUSG00000046223 (Ensembl)
Plce1GeneProductENSMUSG00000024998 (Ensembl)
Plcg1GeneProductENSMUSG00000016933 (Ensembl)
PodxlGeneProductENSMUSG00000025608 (Ensembl)
Ptk2GeneProductENSMUSG00000022607 (Ensembl)
PtproGeneProductENSMUSG00000030223 (Ensembl)
RITUXIMABMetabolite174722-31-7 (CAS)
Scarb2GeneProductENSMUSG00000029426 (Ensembl)
Smarcal1GeneProductENSMUSG00000039354 (Ensembl)
SynpoGeneProductENSMUSG00000043079 (Ensembl)
Tgfb1GeneProductENSMUSG00000002603 (Ensembl)
Tln1GeneProductENSMUSG00000028465 (Ensembl)
Tlr4GeneProductENSMUSG00000039005 (Ensembl)
Trpc6GeneProductENSMUSG00000031997 (Ensembl)
UtrnGeneProductENSMUSG00000019820 (Ensembl)
VclGeneProductENSMUSG00000021823 (Ensembl)
VimGeneProductENSMUSG00000026728 (Ensembl)
VtnGeneProductENSMUSG00000017344 (Ensembl)
WNT1GeneProduct164820 (OMIM)
Wt1GeneProductENSMUSG00000016458 (Ensembl)
YwhaqGeneProductENSMUSG00000076432 (Ensembl)

Annotated Interactions

<cite>No annotated interactions</cite>