Foxp1 Is Required for Renal Intercalated Cell Differentiation and Acid–Base Regulation

Key Points Foxp1 is a key transcriptional factor for the differentiation of intercalated cells in collecting ducts. Dmrt2 and Hmx2 act downstream of Foxp1 to control the differentiation of type A and type B intercalated cells, respectively. Foxp1 and Dmrt2 are essential for body acid–base balance regulation. Background Kidney collecting ducts comprise principal cells and intercalated cells, with intercalated cells playing a crucial role in kidney acid–base regulation through H + and HCO 3 − secretion. Despite its significance, the molecular mechanisms controlling intercalated cell development remain incompletely understood. Methods To investigate the specific role of Foxp1 in kidney tubular system, we specifically deleted Foxp1 expression in kidney distal nephrons and collecting ducts. We examined the effects of Foxp1 on intercalated cell differentiation and urine acidification. RNA sequencing and Chip-seq were used to identify Foxp1 target genes. To dissect the genetic network that regulates intercalated cell differentiation, Dmrt2 -deficient mice were generated to determine the role of Dmrt2 in intercalated cell differentiation. Foxp1 -deficient mice were crossed with Notch2 -deficient mice to dissect the relation between Foxp1 and Notch signaling. Results Foxp1 was selectively expressed in intercalated cells in collecting ducts. The absence of Foxp1 in kidney tubules led to the abolishment of intercalated cell differentiation in the collecting ducts, resulting in distal renal tubular acidosis. Foxp1 regulates the expression of Dmrt2 and Hmx2 , two genes encoding transcription factors specifically expressed in type A and type B intercalated cell cells, respectively. Further genetic analysis revealed that Dmrt2 was essential for type A intercalated cell differentiation, and Foxp1 was necessary downstream of Notch for the regulation of intercalated cell differentiation. Conclusions Foxp1 is required for the renal intercalated cell differentiation and participated in acid–base regulation. Foxp1 regulated downstream transcriptional factors, Dmrt2 and Hmx2, which were involved in the specification of distinct subsets of intercalated cells.