Abstract
Ablation of the Mediator of ErbB2-driven Cell Motility 1 (Memo1) in mice altered calcium homeostasis and renal calcium transporter abundance by an unknown mechanism. Here, we investigated the role of intrarenal Memo in renal calcium handling. We have generated a mouse model of inducible kidney-specific Memo1 deletion. The Memo-deficient mice showed normal serum concentration and urinary excretion of calcium and phosphate, but elevated serum FGF23 concentration. They displayed elevated gene expression and protein abundance of the distal renal calcium transporters NCX1, TRPV5, and calbindin D28k. In addition, Claudin 14 gene expression was increased. When the mice were challenged by a vitamin D deficient diet, serum FGF23 concentration and TRPV5 membrane abundance were decreased, but NCX1 abundance remained increased. Collectively, renal distal calcium transport proteins (TRPV5 and Calbindin-D28k) in this model were altered by Memo- and vitamin-D dependent mechanisms, except for NCX1 which was vitamin D-independent. These findings highlight the existence of distinct regulatory mechanisms affecting TRPV5 and NCX1 membrane expression in vivo.
Highlights
The Mediator of ErbB2-driven Cell Motility (Memo) was discovered in a screen for proteins binding to the phosphorylated ErbB2 receptor (Marone et al, 2004)
We aimed at delineating the physiological involvement of Memo in the adult kidney, without the influence of systemic factors encountered in whole body deletion of Memo
The first finding to highlight is that these mice display normal morphology and have normal life expectancy. This is in sharp contrast with mouse models in which Memo is deleted in the whole body, even during adulthood and which develop premature aging and death
Summary
The Mediator of ErbB2-driven Cell Motility (Memo) was discovered in a screen for proteins binding to the phosphorylated ErbB2 receptor (Marone et al, 2004). We have previously reported a phenotype with traits resembling human aging and altered mineral homeostasis in mice subjected to conditional postnatal deletion of Memo exon 2 (Memo cKO). Renal Memo and Calcium Transporters in the whole body (Haenzi et al, 2014). These mice displayed increased calcemia and 1,25(OH)2-vitamin D3 levels, suppressed parathyroid hormone (PTH) levels, and had a trend to higher serum concentrations of fibroblast growth factor FGF23. Phosphate transporters showed discrete alterations in the kidney of Memo cKO mice, with altered transcription of SLC34a3 and a different cleavage of NaPi2a protein. Memo cKO mice display a specific bone phenotype, resembling partially hypophosphatasia (Moor et al, 2018) and pointing to a role of Memo in the assembly of active alkaline phosphatase dimers
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