Foxp1 Is Required for Renal Intercalated Cell Differentiation and Acid–Base Regulation-Reference-Cited by-同舟云学术

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

Published:2024-02-09 Issue:5 Volume:35 Page:533-548
ISSN:1046-6673
Container-title:Journal of the American Society of Nephrology
language:en
Short-container-title:JASN

Author:

Wu Shi-Ting¹^ORCID,Feng Yu¹^ORCID,Song Renhua²^ORCID,Qi Yanmiao¹^ORCID,Li Lin¹^ORCID,Lu Dongbo¹,Wang Yixuan¹^ORCID,Wu Wenrun³^ORCID,Morgan Angela⁴^ORCID,Wang Xiaohong¹^ORCID,Xia Yin⁵^ORCID,Liu Renjing⁶,Alexander Stephen I.⁷^ORCID,Wong Justin²^ORCID,Zhang Yuzhen³^ORCID,Zheng Xiangjian¹^ORCID

Affiliation:

1. Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, Tianjin, China

2. Epigenetics and RNA Biology Program Centenary Institute and the Faulty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

3. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

4. Murdoch Children's Research Institute, The Royal Children's Hospital and Department of Audiology and Speech Pathology and Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia

5. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

6. Vascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute and School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia

7. Department of Pediatric Nephrology, The Children's Hospital at Westmead and Centre for Kidney Research, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

Abstract

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 HCO3 − 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.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Publisher

Ovid Technologies (Wolters Kluwer Health)

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1. Renal Intercalated Cell Differentiation and Acid–Base Regulation;Journal of the American Society of Nephrology;2024-04-08