Deletion of the transcription factor Prox-1 specifically in the renal distal convoluted tubule causes hypomagnesemia via reduced expression of TRPM6 and NCC

Autor: Johannes Loffing, Dominique Loffing-Cueni, Denise V. Kratschmar, Christina Schnoz, Sandra Moser, Alex Odermatt
Přispěvatelé: University of Zurich, Loffing, Johannes
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Renal distal convoluted tubule (DCT)
10017 Institute of Anatomy
Physiology
Clinical Biochemistry
TRPM Cation Channels
610 Medicine & health
1308 Clinical Biochemistry
Kidney
03 medical and health sciences
Mice
2737 Physiology (medical)
0302 clinical medicine
Physiology (medical)
TRPM6
medicine
Transcriptional regulation
Animals
Magnesium
Solute Carrier Family 12
Member 3
Distal convoluted tubule
Kidney Tubules
Distal
Transcription factor
Solute Carrier Family 12
Member 1
Homeodomain Proteins
Aquaporin 2
NaCl cotransporter (NCC)
Chemistry
Kinase
Tumor Suppressor Proteins
DCT adaptation
Sodium
1314 Physiology
Transient receptor potential cation channel subfamily M member 6 (TRPM6)
Cell biology
body regions
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Transcription factor Prox-1
Potassium
570 Life sciences
biology
Cotransporter
030217 neurology & neurosurgery
Homeostasis
Ion Channels
Receptors and Transporters
Gene Deletion
Zdroj: Pflugers Archiv
ISSN: 1432-2013
0031-6768
Popis: The renal distal convoluted tubule (DCT) is critical for the fine-tuning of urinary ion excretion and the control of blood pressure. Ion transport along the DCT is tightly controlled by posttranscriptional mechanisms including a complex interplay of kinases, phosphatases, and ubiquitin ligases. Previous work identified the transcription factor Prox-1 as a gene significantly enriched in the DCT of adult mice. To test if Prox-1 contributes to the transcriptional regulation of DCT function and structure, we developed a novel mouse model (NCCcre:Prox-1flox/flox) for an inducible deletion of Prox-1 specifically in the DCT. The deletion of Prox-1 had no obvious impact on DCT structure and growth independent whether the deletion was achieved in newborn or adult mice. Furthermore, DCT-specific Prox-1 deficiency did not alter DCT-proliferation in response to loop diuretic treatment. Likewise, the DCT-specific deletion of Prox-1 did not cause other gross phenotypic abnormalities. Body weight, urinary volume, Na+ and K+ excretion as well as plasma Na+, K+, and aldosterone levels were similar in Prox-1DCTKO and Prox-1DCTCtrl mice. However, Prox-1DCTKO mice exhibited a significant hypomagnesemia with a profound downregulation of the DCT-specific apical Mg2+ channel TRPM6 and the NaCl cotransporter (NCC) at both mRNA and protein levels. The expression of other proteins involved in distal tubule Mg2+ and Na+ handling was not affected. Thus, Prox-1 is a DCT-enriched transcription factor that does not control DCT growth but contributes to the molecular control of DCT-dependent Mg2+ homeostasis in the adult kidney.
Databáze: OpenAIRE
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