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

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 (NCC^cre:Prox-1^flox/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-1_DCT^KO and Prox-1_DCT^Ctrl mice. However, Prox-1_DCT^KO 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.

SUBMITTER: Schnoz C 

PROVIDER: S-EPMC7782375 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature