Abstract
The mechanism underlying phosphatidylserine eversion in renal tubule cells following calcium oxalate-mediated damage remains unclear; therefore, we investigated the effects of TGF-β1/Smad signaling on phosphatidylserine eversion in the renal tubule cell membrane during the early stage of kidney stone development. In a rat model of early stage of calcium oxalate stone formation, phosphatidylserine eversion on the renal tubular cell membrane was detected by flow cytometry, and the expression of TGF-β1 (transforming growth factor-β1), Smad7, and phospholipid scramblase in the renal tubular cell membrane was measured by western blotting. We observed that the TGF-β1/Smad signaling pathway increased phosphatidylserine eversion at the organism level. The results of in vitro studies demonstrated that oxalate exposure to renal tubule cells induced TGF-β1 expression, increasing phospholipid scramblase activity and phosphatidylserine eversion in the renal tubule cell membrane. These results indicate that TGF-β1 stimulates phosphatidylserine eversion by increasing the phospholipid scramblase activity in the renal tubule cell membrane during the early stage of kidney stone development. The results of this study form a basis for further detailed research on the development of therapeutic agents that specifically treat urolithiasis and exert fewer adverse effects.
Highlights
Urolithiasis is one of the most common diseases affecting humans and is associated with multiple urological complications [1]
Previous studies have showed that a high concentration of calcium oxalate leads to the overproduction of reactive oxygen species (ROS) [7], which subsequently contributes to PS externalization in renal tubule cells to result in nucleation and growth of CaOx crystals [8]
To establish a rat model of early stage kidney stone formation, ethylene glycol and ammonium chloride were administered to the stomach of rats for 2 weeks, and each kidney section was examined with a digital microscope
Summary
Urolithiasis is one of the most common diseases affecting humans and is associated with multiple urological complications [1]. Calcium oxalate(CaOx) reportedly injures cultured renal tubular cells, after which cell membrane phosphatidylserine (PS) flips from the inner layer to the outer layer in vitro to play important roles in kidney stone formation [2]. The mechanism underlying PS externalization in renal tubule cells caused by CaOx-mediated damage remains unclear. Previous studies have showed that a high concentration of calcium oxalate leads to the overproduction of reactive oxygen species (ROS) [7], which subsequently contributes to PS externalization in renal tubule cells to result in nucleation and growth of CaOx crystals [8]. ROS and lipid peroxidation strongly activate phospholipid scramblase (PLSCR) [9], whereas exposure to ROS scavengers, such as glutathione, coenzyme Q10, or idebenone (a synthetic coenzyme Q10 homolog), reduces the activation of PLSCR in polycystic kidney disease [10].
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