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

doi:10.1681/ASN.2020020184

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Visual Abstract

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. Cdh6^high, lotus tetragonolobus lectin-low (LTL^low) cells serve as PT progenitors and demonstrate higher proliferation than Cdh6^low, LTL^high 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.

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