Lead (Pb)-induced calcium oxalate crystallization ex vivo is ameliorated via inositol 1,4,5-trisphosphate receptor (InsPR) knockdown in a Drosophila melanogaster model of nephrolithiasis.

Nephrolithiasis causes severe pain and is a highly recurrent pathophysiological state. Calcium-containing stones, specifically calcium oxalate (CaOx), is the most common type accounting for approximately 75 % of stone composition. Genetic predisposition, gender, geographic region, diet, and low fluid intake all contribute to disease pathogenesis. However, exposure to environmental pollutants as a contribution to kidney stone formation remains insufficiently studied. Lead (Pb2+) is of particular interest as epidemiological data indicate that low-level exposure (BLL = 0.48-3.85 μM) confers a 35 % increased risk of developing CaOx nephrolithiasis. However, mechanisms underlying this association have yet to be elucidated. Drosophila melanogaster provide a useful genetic model where major molecular pathophysiological pathways can be efficiently studied. Malpighian tubules (MT) were isolated from either Wild-Type or InsPR knockdown flies and treated with oxalate (5 mM) ± Pb (2μM) for 1 h. Following exposure, MTs were imaged and crystals quantified. CaOx crystal number and total area were significantly increased (˜5-fold) in Pb(pre-treatment) + oxalate-exposed MTs when compared to oxalate alone controls. However, CaOx crystal number and total crystal area in Pb + oxalate-exposed InsPR knockdown MTs were significantly decreased (˜3-fold) indicating the role for principal cell-specific InsPR-mediated Ca mobilization as a mechanism for Pb-induced increases in CaOx crystallization inset model of nephrolithiasis.