Loss of the mediator Of cell motility 1 ( Memo1 ) in mice caused kidney disease and a bone disease with diminished osteoblast and osteoclast biomarkers in serum, resembling alterations occurring in adynamic bone disease in humans with chronic kidney disease or in Klotho‐deficient mice. Here, we investigated whether Memo1 expression in osteoblasts is required for normal bone structure and FGF23 expression. We deleted Memo1 in the osteoblast–osteocyte lineage in Memo fl/fl mice using a Cre under Col1a1 promotor to obtain osteoblast‐specific knockout (obKO) mice. We studied organs by micro‐computed tomography, qPCR, and western blot. We challenged mice with folic acid for acute kidney injury (AKI) and analyzed organs. Memo obKO were viable without changes in gross anatomy, serum electrolytes, or circulating FGF23 concentrations compared to controls. Memo1 expression was blunted in bones of Memo obKO, whereas it remained unchanged in other organs. Micro‐CT revealed no differences between genotypes in bone structure of vertebrae, femur, and tibia. During AKI, Fgf23 expression in calvaria, and renal transcriptional changes were comparable between genotypes. However, renal injury marker expression, circulating FGF23, and parathyroid hormone revealed a sex difference with more severely affected females than males of either genotype. The present data imply that Memo1 in osteoblasts is dispensable for bone structure and expression of Fgf23 . Moreover, we found evidence of potential sex differences in murine folic acid nephropathy similar to other experimental models of renal injury that are important to consider when using this experimental model of renal injury.
Memo promotes receptor tyrosine kinase (RTK) signaling by unknown mechanisms. Memo1 deletion in mice causes premature aging and unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. Here, we report a role for Memo’s redox function in FGF23-driven RTK signaling in the kidney. Postnatally Memo-deficient (cKO) and floxed controls were treated with FGF23 or vehicle, followed by molecular and biochemical analyses. Findings were validated using cell culture and recombinant proteins. Memo cKO mice showed impaired renal ERK phosphorylation and transcriptional responses to FGF23. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1). Renal RhoA abundance and activity were increased in Memo cKO. Immunoprecipitation analysis showed an association between Memo and Rho-GDI1. We confirmed an interaction between the two proteins, with Memo-dependent irreversible oxidation at Rho-GDI1 Cys79 in cell-free conditions. Collectively, our findings reveal that redox protein Memo promotes renal FGF23 signaling together with oxidative modulation of the Rho-GTPase network.
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