Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS

Maezawa, Yoshiro; Onay, Tuncer; Scott, Rizaldy P.; Keir, Lindsay; Dimke, Henrik; Li, Chengjin; Eremina, Vera; Maezawa, Yoshiro; Jeansson, Marie; Shan, Jingdong; Binnie, Matthew; Lewin, Moshe; Ghosh, Asish K.; Miner, Jeffrey H.; Vainio, Seppo; Quaggin, Susan E.

doi:10.1681/asn.2013121307

Cited by 54 publications

(51 citation statements)

References 31 publications

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“…Deletion of Tcf21 from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively, caused loss of Tcf21 from capillary-loop stage podocytes (podTcf21), resulting in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to those of FSGS [78] (Table 2; Fig. 1).…”

Section: Transcription Factor 21 (Pod1) Modelmentioning

confidence: 91%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

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Section: Transcription Factor 21 (Pod1) Modelmentioning

confidence: 91%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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“…Indeed, MAFB/Kreisler, TCF21/POD1, LMX1B, and the FoxC-class TFs have already been shown to be of relevance in podocytes. [15][16][17][18][19] Frequently, networks of TFs cooperatively control gene expression by binding in TF modules to enhancers. These tissuespecific DNA-regulatory elements are located distally from the TSS.…”

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

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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“…Podocyte injury is considered to be one of the most critical factors in the development of proteinuria caused by glomerular filtration barrier dysfunction and continuous injury may cause severe apoptosis, leading to proteinuria, glomerulosclerosis and renal impairment; the major reason is that podocytes are highly differentiated cells with specific structural and biological functions, which are not renewable after sustained injury (1,2). To date, a large number of studies have indicated that podocyte injury, loss and dysfunction have an important role in pathologies including focal segmental glomerulosclerosis and membranous nephropathy (3)(4)(5). Immunosuppressants (e.g., steroids or cyclosporine A) have been used based on anecdotal evidence to treat NS (6).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of astragalosides from Radix Astragali on adriamycin-induced podocyte injury

et al. 2018

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Abstract. Nephrotic syndrome (NS) is the most common kidney disease in clinical practice and may lead to end-stage renal failure. Astragalosides (AST) have been clinically tested for the treatment of NS, but their mechanism of action has remained to be elucidated. The aim of the present study was to investigate the effect of AST on the structure and function of podocytes with adriamycin (ADR)-induced damage and to elucidate the underlying molecular mechanisms. The mouse podocyte clone 5 (MPC5) immortalized mouse podocyte cell line was treated with 0.5 µmol/l ADR to establish a podocyte injury model. The MPC5 podocytes were divided into a control group, a podocyte injury group and a low-, medium-and high-concentration AST treatment group. The results indicated that the survival rate of the podocyte injury group was significantly decreased compared with that in the control group and each AST-treated group had an increased survival rate compared with that in the podocyte injury group. Furthermore, each dose of AST significantly inhibited the ADR-associated increases the levels of lactate dehydrogenase and malondialdehyde and the decrease in the activity of superoxide dismutase in MPC5 podocytes. In addition, AST improved the migration ability of MPC5 podocytes and suppressed the cytoskeletal rearrangement associated with ADR-induced damage. Furthermore, matrix metalloproteinase (MMP)-2 and -9 were decreased in the podocyte injury group, which was inhibited by different concentrations of AST. Thus, AST was able to maintain the balance of oxidative stress in podocytes cultured with ADR and protect them from ADR-induced injury. The mechanism may be associated with the upregulation of MMPs.

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Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS

Cited by 54 publications

References 31 publications

Recent advances of animal model of focal segmental glomerulosclerosis

Recent advances of animal model of focal segmental glomerulosclerosis

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

Protective effect of astragalosides from Radix Astragali on adriamycin-induced podocyte injury

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