Kidney stones represent a significant clinical issue affecting approximately 10% of the global population, with no available treatment. Drinking more water is effective in reducing kidney stone occurrence by increasing urinary flow and decreasing ion supersaturation.

In this study, we investigated Ca-oxalate (CaOx) crystal formation in *Drosophila* Malpighian tubules (MT) to determine whether genetic manipulation of water channels (Drip, Prip) and a salt transporter (NDAE1) in stellate cells could influence crystal formation. F1-knockdowns were generated by crossing 724-GAL4 flies with UAS-RNAi lines targeting Drip, Prip, and NDAE1. The resulting F1 flies were fed food supplemented with 10 mM NaOx for 4 days. MTs were then dissected, and fixed on slides, and CaOx crystals were quantified using birefringence via polarizing microscopy.

Previous studies have demonstrated that MTs secrete fluid at a faster rate on a per-cell basis than any other epithelium. Drip and Prip exhibit significant water permeability when expressed in *Xenopus* oocytes, and knockdowns of Drip and Prip lead to decreased fluid secretion and increased crvstal formation.

Our updated findings indicate that knockdowns of Drip, Prip, and NDAE1 result in statistically significant increases in both the number and surface area of CaOx crystals compared to control. This suggests that NDAEI-mediated ion transport supports transepithelial water movement and helps maintain dilute MT secretions, preventing crystal formation. Together, these results highlight that both AQP-mediated water transport and salt-driven water transport mechanisms are crucial in maintaining the dilutive capacity of MT secretions to avoid crystal formation. These findings also suggest that developing therapeutics to enhance urine flow, such as aquaretics, may offer new options for preventing kidney stone disease, especially when increased water intake alone is insufficient.