Kidney stone is one of the most frequent urinary tract diseases, affecting 10% of the population and displaying a high recurrence rate. Kidney stones are the result of salt supersaturation, including calcium and oxalate. We have previously identified Esophageal cancer-related gene 4 (Ecrg4) as being modulated by hypercalciuria. Ecrg4 was initially described as a tumor suppressor gene in the esophagus. Lately, it was shown to be involved as well in apoptosis, cell senescence, cell migration, inflammation and cell responsiveness to chemotherapy. To the best of our knowledge, nothing is known about ECRG4’s function in the renal tissue and its relationship with calciuria. We hypothesized that the increased expression of Ecrg4 mRNA is triggered by hypercalciuria and might modulate intratubular calcium-oxalate precipitation. In this study, we have first (i) validated the increased Ecrg4 mRNA in several types of hypercalciuric mouse models, then (ii) described the Ecrg4 mRNA expression along the nephron and (iii) assessed ECRG4’s putative role in calcium oxalate nephropathy. For this, Ecrg4 KO mice were challenged with a kidney stone-inducing diet, rich in calcium and oxalate precursor. Taken together, our study demonstrates that Ecrg4’s expression is restricted mainly to the distal part of the nephron and that the Ecrg4 KO mice develop less signs of tubular obstruction and less calcium-oxalate deposits. This promotes Ecrg4 as a modulator of renal crystallization and may open the way to new therapeutic possibilities against calcium oxalate nephropathy.

Background Evidence point at Xenotropic and Polytropic retrovirus Receptor 1 (XPR1) as a protein involved in the cellular phosphate export pathway and phosphate homeostasis: systemic constitutive deletion of Xpr1 in mice is lethal and kidney‐specific deletion of Xpr1 induces hypophosphatemic rickets with hypercalciuria. XPR1 is expressed in the bone, but its function remains elusive. We hypothesized that XPR1 is crucial for bone homeostasis and that is involved in the sensing mechanism of phosphate in the bone. Methods We established an inducible whole body Xpr1 KO mouse model. The mice were placed in metabolic cages for urine and blood analysis, followed by femur uCT and histomorphometry. The Fgf23 mRNA and protein (c‐terminal and intact FGF23) levels were assessed from tibia and femur incubated ex vivo for 24h with increasing phosphate concentrations. Primary osteoblast cells were isolated from control and Xpr1 KO mouse calvaria. Results Conditional total body Xpr1KO mice are constantly decreasing their body weight upon Xpr1 deletion, and develop profound hypophosphatemia, compared to their control littermates. Histomorphometry analysis and uCT on femurs of Xpr1 KO mice show high trabecular bone density, despite low bone formation rate and low number of osteoclasts. Increased intact FGF23 secretion by tibia and femur was observed in control mice in response to increased phosphate concentration in the media. However, the bone samples from Xpr1KO mice are resistant to phosphate induced FGF23 secretion. No changes were observed for the c‐terminal FGF23 in response to increased phosphate concentration, for both the control and Xpr1 KO mice. Osteoblasts were successfully prepared from control and Xpr1 KO mouse calvarie and Xpr1 expression was inactivated by tamoxifen treatment. Conclusion XPR1 is essential for phosphate homeostasis and FGF23 secretion upon phosphate exposure. Osteoblasts will now be used to further study phosphate dependent FGF23 secretion.