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Basic Research
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Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney

Sierra S. Marable, Eunah Chung and Joo-Seop Park
JASN November 2020, 31 (11) 2543-2558; DOI: https://doi.org/10.1681/ASN.2020020184
Sierra S. Marable
1Division of Pediatric Urology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
2Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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Eunah Chung
1Division of Pediatric Urology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
2Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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Joo-Seop Park
1Division of Pediatric Urology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
2Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
3Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Significance Statement

Proximal tubule cells are the most abundant cell type in the mammalian kidney, and they perform the bulk of the renal reabsorption function. Despite the importance of these cells in kidney function, the molecular mechanisms of proximal tubule development and maturation are not well understood. Experiments reveal that, in the developing mouse kidney, Cadherin-6-expressing cells act as proximal tubule progenitors and they require Hnf4a to further develop into mature proximal tubules. Genomic analyses show that Hnf4a directly regulates the expression of genes required for reabsorption, such as transmembrane transporter genes and metabolism genes. This study advances understanding of how kidney proximal tubule cells form during development.

Abstract

Background Hepatocyte NF 4α (Hnf4a) is a major regulator of renal proximal tubule (PT) development. In humans, a mutation in HNF4A impairs PT functions and is associated with Fanconi renotubular syndrome (FRTS). In mice, mosaic deletion of Hnf4a in the developing kidney reduces the population of PT cells, leading to FRTS-like symptoms. The molecular mechanisms underlying the role of Hnf4a in PT development remain unclear.

Methods The gene deletion tool Osr2Cre removed Hnf4a in developing nephrons in mice, generating a novel model for FRTS. Immunofluorescence analysis characterized the mutant phenotype, and lineage analysis tested whether Cadherin-6 (Cdh6)–expressing cells are PT progenitors. Genome-wide mapping of Hnf4a binding sites and differential gene analysis of Hnf4a mutant kidneys identified direct target genes of Hnf4a.

Results Deletion of Hnf4a with Osr2Cre led to the complete loss of mature PT cells, lethal to the Hnf4a mutant mice. Cdh6high, lotus tetragonolobus lectin-low (LTLlow) cells serve as PT progenitors and demonstrate higher proliferation than Cdh6low, LTLhigh differentiated PT cells. Additionally, Hnf4a is required for PT progenitors to differentiate into mature PT cells. Genomic analyses revealed that Hnf4a directly regulates the expression of genes involved in transmembrane transport and metabolism.

Conclusions Hnf4a promotes the differentiation of PT progenitors into mature PT cells by regulating the expression of genes associated with reabsorption, the major function of PT cells.

  • proximal tubule
  • Hnf4a
  • kidney development
  • Fanconi renotubular syndrome
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (11)
Journal of the American Society of Nephrology
Vol. 31, Issue 11
November 2020
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Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney
Sierra S. Marable, Eunah Chung, Joo-Seop Park
JASN Nov 2020, 31 (11) 2543-2558; DOI: 10.1681/ASN.2020020184

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Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney
Sierra S. Marable, Eunah Chung, Joo-Seop Park
JASN Nov 2020, 31 (11) 2543-2558; DOI: 10.1681/ASN.2020020184
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More in this TOC Section

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  • A Comprehensive Map of mRNAs and Their Isoforms across All 14 Renal Tubule Segments of Mouse
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Keywords

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  • Hnf4a
  • kidney development
  • Fanconi renotubular syndrome

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