Primary Focal Segmental Glomerulosclerosis FSGS (Mus musculus)

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1-7PTT: Therapeutic Target (decrease)P13KCALCIUMAD: Autosomal RecessiveACTINSLIT DIAPHRAGMDISRUPTIONACTINPKAAR: Autosomal Dominant+CALCINEURINF-ACTINMICRORNA 193ALegendTT: Therapeutic Target (increase)APOPTOSIS3P21PODOCYTOPENIAPodocyte-Associated Genetic Glomerular DiseasesPROTEIN17Q25GENEARSTABILIZES PODOCYTECYTOSKELETONMATERNAL10Q23PRIMARY INJURYESRDARARNUCLEUS11P15.5NonsyndromicSyndromicPRIMARY FSGSAR15Q21-Q229Q33.3TYPE4Q21.1Itgb3Akt1VtnIrf6Kirrel3SynpoFynCd151Nck1AgrnPlaurPtproYwhaqDkk1Lama5Ptk2Tgfb1Camk2bItgavCtslKirrel2VclTlr4Jag1Dnm1Cd2apCsAKrt8Nphs2Lamb2Nphs1Plcg1Cdkn1bRITUXIMABCr1lPax2PodxlLmx1bMyo1eScarb2MT-TL1Myo1eFat1Lmx1bItgb4MT-TL1Col4a5Cdkn1cMmeMYCOPHENOLATE MOFETILVimCdkn1aCd151PodxlNphs1Plce1Cd2apACTN4Myh9Smarcal1Wt1Inf2Trpc6ACTN4Cd2apPlce1Nphs2Nphs1Myh9Smarcal1Wt1Inf2Trpc61Q25-Q3119Q136P12.311P132Q3519Q13.122Q12.311Q21-2214QCHROMOSOMETRANSMISSIONARARADAD/ARADADADARCOMPLEXLamb2Itgb4Cd151ARScarb2ARADWt1PcnaMki67Cdh2Cldn1DESTRUCTION OFPODOCYTEARCHITECTURENUCLEUSPODOCYTETTWt1SynpoCol4a3Col4a4ACTN4GLOMERULAR BASEMENT MEMBRANENORMAL PODOCYTELims1Nphs1Nphs2Cd80Notch1+P-SynpoGLOMERULAR BASEMENT MEMBRANETTTTTTTTTTTTTTTTTTTTTTTTTTCtnnb1Notch1Lrp6Lrp5TTTTTTTrpc6TTTTTTTTTTTTTTTTTTTTTTGLOMERULAR BASEMENT MEMBRANENORMALEPITOPESPAXTTANTICLA4TTTln1IlkItgb1Itga3Proteins involved in Podocyte cytoskeletonDag1PARVAIlkUtrnWNT1Y-SECRETASE


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 Europe PMC Scholia
  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 Europe PMC Scholia
  3. Rood IM, Deegens JK, Wetzels JF; ''Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice.''; Nephrol Dial Transplant, 2012 PubMed Europe PMC Scholia
  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 Europe PMC Scholia
  6. Kato H, Susztak K; ''Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis.''; Semin Nephrol, 2012 PubMed Europe PMC Scholia
  7. Reiser J, Gupta V, Kistler AD; ''Toward the development of podocyte-specific drugs.''; Kidney Int, 2010 PubMed Europe PMC Scholia


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97540view14:33, 24 May 2018DeSlAnother Entrez to Entrez Gene
97537view14:32, 24 May 2018DeSlChanged Database from Entrez to Entrez Gene.
97535view14:30, 24 May 2018DeSlAACTININ4 should be ACTN4 (according to original OMIM ID). Added Ensembl ID for it now.
97533view14:26, 24 May 2018DeSlChanged PARVA ID from OMIM to Ensembl
97531view14:24, 24 May 2018DeSlChanged MT-TL1 ID from OMIM to Entrez
97529view14:21, 24 May 2018DeSlChanged ID for ACTN4 from OMIM to ENSEMBL
97504view13:29, 24 May 2018MaxvansonChanged some identifiers for better linking to other databases
89874view12:51, 6 October 2016MkutmonModified description
79651view11:44, 1 April 2015EgonwUpdated the Ensembl data source names.
78429view10:26, 7 January 2015MaintBotadded missing graphIds
72201view11:12, 27 October 2013EgonwFixed the PubChem-compound database name.
71216view20:25, 14 October 2013DMicaelSpecify description
71215view20:21, 14 October 2013DMicaelSpecify description
71206view17:49, 14 October 2013DMicaelSpecify description
71151view21:12, 10 October 2013MaintBotone more publication ref
71150view21:11, 10 October 2013MaintBotfixed remaining publication refs
71149view20:48, 10 October 2013MaintBotFixed publication
71101view17:07, 4 October 2013DMicaelModified description
71100view17:06, 4 October 2013DMicaelModified title
71086view21:58, 3 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71085view17:19, 3 October 2013DMicaelOntology Term : 'CL:1001005' removed !
71082view02:31, 3 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71081view02:29, 3 October 2013DMicaelOntology Term : 'glomerular capillary endothelial cell' added !
71079view02:00, 3 October 2013DMicaelModified title
71076view17:10, 2 October 2013DMicaelOntology Term : 'renal failure pathway' added !
71075view17:03, 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

No annotated interactions

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