The role of the podocyte in albumin filtration

Brinkkoetter, Paul T.; Ising, Christina; Benzing, Thomas

doi:10.1038/nrneph.2013.78

Cited by 191 publications

(154 citation statements)

References 140 publications

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“…Alteration of the intercellular junctions and cytoskeletal structure of podocytes or their detachment from the membrane results in the development of albuminuria. 47 Interestingly, WT1 direct target genes in podocytes were enriched for regulation of actin cytoskeleton, focal adhesion, tight junction, and adherens junction, indicating that WT1 is a central regulator of podocyte architecture. This is corroborated by the podocyte-specific WT1 knockout mouse model that we used, where the loss of WT1 affected podocyte differentiation and led to kidney failure and death within 24 hours after birth.…”

Section: Discussionmentioning

confidence: 99%

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms’ Tumor 1 Target Genes in Podocyte Differentiation and Maintenance

Dong¹,

Pietsch²,

Tan³

et al. 2015

Journal of the American Society of Nephrology

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The Wilms' tumor suppressor gene 1 (WT1) encodes a zinc finger transcription factor. Mutation of WT1 in humans leads to Wilms' tumor, a pediatric kidney tumor, or other kidney diseases, such as Denys-Drash and Frasier syndromes. We showed previously that inactivation of WT1 in podocytes of adult mice results in proteinuria, foot process effacement, and glomerulosclerosis. However, the WT1-dependent transcriptional network regulating podocyte development and maintenance in vivo remains unknown. Here, we performed chromatin immunoprecipitation followed by high-throughput sequencing with glomeruli from wild-type mice. Additionally, we performed a cDNA microarray screen on an inducible podocyte-specific WT1 knockout mouse model. By integration of cistromic and transcriptomic analyses, we identified the WT1 targetome in mature podocytes. To further analyze the function and targets of WT1 in podocyte maturation, we used an Nphs2-Cre model, in which WT1 is deleted during podocyte differentiation. These mice display anuria and kidney hemorrhage and die within 24 hours after birth. To address the evolutionary conservation of WT1 targets, we performed functional assays using zebrafish as a model and identified Nphs2, Mafb, and Magi2 as novel WT1 target genes required for podocyte development. Our data also show that both Mafb and Magi2 are required for normal development of the embryonic zebrafish kidney. Collectively, our work provides insights into the transcriptional networks controlled by WT1 and identifies novel WT1 target genes that mediate the function of WT1 in podocyte differentiation and maintenance.

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Section: Discussionmentioning

confidence: 99%

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms’ Tumor 1 Target Genes in Podocyte Differentiation and Maintenance

Dong¹,

Pietsch²,

Tan³

et al. 2015

Journal of the American Society of Nephrology

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“…The filtration barrier of the kidney is a highly specialized structure, composed of glomerular endothelial cells, glomerular basement membrane, and interdigitating podocyte foot processes bridged by the slit diaphragm protein complex (16). The integrity of this barrier to maintain ultrafiltration of plasma depends on the proper expression and signaling of the components of the slit diaphragm (16)(17)(18). Several mutations in the gene that encodes nephrin (NPHS1), and other components of the slit diaphragm complex, have been described in patients with congenital nephrotic syndrome (14,19).…”

Section: Magi-2/s-scam | Glomerulosclerosismentioning

confidence: 99%

MAGI-2 scaffold protein is critical for kidney barrier function

Balbas¹,

Burgess

Murali

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss.

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“…Most disorders affect the glomerular podocytes, terminally differentiated and highly polarized cells that require tightly controlled signaling to maintain their integrity, viability, and function. 1 Although the most abundant podocyte transcription factor (TF), Wilms' tumor suppressor 1 (WT1), was identified as a key podocyte regulator, 2-4 the WT1-controlled transcriptional podocyte network is poorly understood.…”

mentioning

confidence: 99%

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

Kann¹,

Ettou²,

Jung

et al. 2015

Journal of the American Society of Nephrology

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108

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The transcription factor Wilms' tumor suppressor 1 (WT1) is key to podocyte development and viability; however, WT1 transcriptional networks in podocytes remain elusive. We provide a comprehensive analysis of the genome-wide WT1 transcriptional network in podocytes in vivo using chromatin immunoprecipitation followed by sequencing (ChIPseq) and RNA sequencing techniques. Our data show a specific role for WT1 in regulating the podocyte-specific transcriptome through binding to both promoters and enhancers of target genes. Furthermore, we inferred a podocyte transcription factor network consisting of WT1, LMX1B, TCF21, Fox-class and TEAD family transcription factors, and MAFB that uses tissue-specific enhancers to control podocyte gene expression. In addition to previously described WT1-dependent target genes, ChIPseq identified novel WT1-dependent signaling systems. These targets included components of the Hippo signaling system, underscoring the power of genome-wide transcriptional-network analyses. Together, our data elucidate a comprehensive gene regulatory network in podocytes suggesting that WT1 gene regulatory function and podocyte cell-type specification can best be understood in the context of transcription factor-regulatory element network interplay.

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The role of the podocyte in albumin filtration

Cited by 191 publications

References 140 publications

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms’ Tumor 1 Target Genes in Podocyte Differentiation and Maintenance

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms’ Tumor 1 Target Genes in Podocyte Differentiation and Maintenance

MAGI-2 scaffold protein is critical for kidney barrier function

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

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