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. 2022 Feb;50(1):11-20.
doi: 10.1007/s00240-021-01292-0. Epub 2021 Dec 3.

Phosphatidylserine eversion regulated by phospholipid scramblase activated by TGF-β1/Smad signaling in the early stage of kidney stone formation

Xiu Guo Gan  1 , Hai Tao Xu  2 , Zhi Hao Wang  2
Affiliations

Phosphatidylserine eversion regulated by phospholipid scramblase activated by TGF-β1/Smad signaling in the early stage of kidney stone formation

Xiu Guo Gan et al. Urolithiasis. 2022 Feb.

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.

Keywords: Kidney stone; Phosphatidylserine; Phospholipid scramblase; TGF-β1.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Crystal formation and PS externalization observed in the control, kidney stone, and kidney stone + SB431542 groups. (A) Crystal formation in the renal tissue on day 14; arrow indicates microcrystalline structures. (B) MDCK cells observed by confocal laser microscopy. (C) Flow cytometric plots of eversion rate. (D) Eversion rate (%). Triangle indicates P < 0.05 vs. control. Asterisk indicates P < 0.05 vs. kidney stone group
Fig. 2
Fig. 2
TGF-β1/Smad expression in the control, kidney stone, and kidney stone + SB431542 groups, and PLSCR expression in the renal tubule cell membrane. (A) TGF-β1/Smad expression. (B) Relative phospholipid scramblase (PLSCR) levels, and representative blot with expression normalized to that of GAPDH. P < 0.05. Triangle indicates P < 0.05 vs. control. Round dot indicates P < 0.05 vs. CaOx group. Pound sign indicates P < 0.05 vs. TGF-β1 group
Fig. 3
Fig. 3
Rate of inward and outward movements of NBD-PS. (A) Comparison among the control, oxalate calcium, and anti-TGF-β1 + oxalate calcium groups. (B) Comparison among the calcium oxalate, negative + calcium oxalate, and siRNA-PLSCR + calcium oxalate groups. (C) Comparison among the control, TGF-β1, and siRNA-PLSCR + TGF-β1 groups. Triangle indicates P < 0.05 vs. control. Round dot indicates P < 0.05 vs. CaOx group. Pound sign indicates P < 0.05 vs. TGF-β1 group
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