Abstract: TH-OR63
Foxp1/Dmrt2/Hmx2 Transcriptional Network Regulates Intercalated Cell Differentiation in Kidney Collecting Ducts
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Back to the Basics
October 24, 2024 | Location: Room 4, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Zheng, Xiangjian, Tianjin Medical University, Tianjin, China
- Feng, Yu, Tianjin Medical University, Tianjin, China
- Qi, Yanmiao, Tianjin Medical University, Tianjin, China
Background
Kidney collecting ducts are comprised of principal cells (PCs) and intercalated cells (ICs), with ICs playing a crucial role in kidney acid-base regulation through H+ and HCO3- secretion. Despite its significance, the molecular mechanisms controlling IC development remain incompletely understood. Single cell sequencing analysis found Foxp1 is selective expressed in ICs relative to PCs, DMRT2 and HMX2 are selective expressed in type-A ICs and type-B ICs respectively.
Methods
To investigate the specific role of Foxp1 and its downstream trascriptional factors in kidney tubular system, we specifically deleted Foxp1 expression in kidney distal nephrons and collecting ducts. We examined the effects of Foxp1 on IC differentiation and urine acidification. RNA sequencing and Chip-seq were used to identify Foxp1 target genes. To dissect genetic network regulates IC differentiation, Dmrt2 and Hmx2-deficient mice were generated to determine the role of Dmrt2 and Hmx2 in IC differentiation. Foxp1 deficient mice were cross with Notch2 deficient mice to dissect the relation between Foxp1 and Notch signaling.
Results
Immunostainings confirmed Foxp1 is selectively expressed in ICs in collecting ducts. Absence of Foxp1 in kidney tubules led to the abolishment of IC differentiation in the collecting ducts, resulting in distal renal tubular acidosis. ChIP-seq and Ribo-Seq analysis found that Foxp1 binds to the promoters of Hmx2 and Dmrt2, two genes encoding transcription factors specifically expressed in type-A and -B ICs, respectively, and promotes their expression. Genetic disruption of Dmrt2 and Hmx2 expression blocks type-A and type-B IC differentiation, respectively. Deletion of Foxp1 blocks the excessive IC differentiation driven by loss-of-function of Notch2, but conditional knockin of Foxp1 do not alter the balance of PC/IC ratio in collecting ducts.
Conclusion
Foxp1 is required at the downstream of Notch signaling for the renal ICs differentiation and participated in acid-base regulation. Foxp1 regulated downstream transcriptional factors, Dmrt2 and Hmx2, which involved in the specification of distinct subsets of ICs.