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

Abstract

Hepatocyte NF 4α (Hnf4a) is a major regulator of renal proximal tubule (PT) development. In humans, a mutation in <i>HNF4A</i> impairs PT functions and is associated with Fanconi renotubular syndrome (FRTS). In mice, mosaic deletion of <i>Hnf4a</i> 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. The gene deletion tool <i>Osr2Cre</i> removed <i>Hnf4a</i> 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 <i>Hnf4a</i> mutant kidneys identified direct target genes of Hnf4a. Deletion of <i>Hnf4a</i> with <i>Osr2Cre</i> led to the complete loss of mature PT cells, lethal to the <i>Hnf4a</i> 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. 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.