Lead (Pb2+)-induced calcium oxalate crystallization ex vivo is ameliorated via inositol 1,4,5-trisphosphate receptor (InsP3R) 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 mu M) 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 InsP(3)R knockdown flies and treated with oxalate (5 mM) +/- Pb2+ (2 mu M) for 1 h. Following exposure, MTs were imaged and crystals quantified. CaOx crystal number and total area were significantly increased (5-fold) in Pb2+(pre-treatment) + oxalate-exposed MTs when compared to oxalate alone controls. However, CaOx crystal number and total crystal area in Pb2+ + oxalate-exposed InsP3R knockdown MTs were significantly decreased (3-fold) indicating the role for principal cell-specific InsP(3)R-mediated Ca2+ mobilization as a mechanism for Pb2+-induced increases in CaOx crystallization inset model of nephrolithiasis.

Automated summary

Nephrolithiasis, particularly calcium oxalate stones, causes severe pain and is highly recurrent. Environmental pollutants, such as lead, may increase the risk of calcium oxalate nephrolithiasis. Fruit fly models suggest that lead-induced increases in CaOx crystallization could be involved in kidney stone formation.