2020
Pflugers Arch. 2020 Nov 16. doi: 10.1007/s00424-020-02491-1. Online ahead of print.
Deletion of the transcription factor Prox-1 specifically in the renal distal convoluted tubule causes hypomagnesemia via reduced expression of TRPM6 and NCC
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. National Centre of Competence in Research "Kidney.CH", University of Zurich, 8057, Zurich, Switzerland.
Service type: Knock-in mice
Abstract
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. Keywords: DCT adaptation; Kidney; NaCl cotransporter (NCC); Renal distal convoluted tubule (DCT); Transcription factor Prox-1; Transient receptor potential cation channel subfamily M member 6 (TRPM6).
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