Inhibitory Effect of Solute Carrier Family 7 Member 5 Inhibitor JPH203 on Renal Fibrosis Induced by Unilateral Ureteral Obstruction in Mice

doi:10.12300/j.issn.1674-5817.2025.092

Abstract

Abstract:

Objective To investigate the effect of solute carrier family 7 member 5 (SLC7A5) inhibitor JPH203 on renal fibrosis induced by unilateral ureteral obstruction in mice. Methods Sixteen SPF male C57BL/6 mice were randomly divided into the control group and the experimental group, with 8 mice in each group. The mouse model of renal fibrosis was established by unilateral ureteral obstruction. From the third day after surgery, the mice in the control group were intraperitoneally injected with phosphate-buffered saline (PBS) for 11 consecutive days, and the injection dose was 200 μL/d. Mice in the experimental group received intraperitoneal injection of JPH203 (50 mg/kg) every day for 11 days. On day 14, the mice were euthanized, then the kidney tissues were obtained. Hematoxylin and eosin (HE) staining was used to assess renal tissue damage, Masson staining was used to evaluate collagen fiber deposition in the extracellular matrix, and immunohistochemistry was used to detect the levels of fibroblast activation markers α-smooth muscle actin (α-SMA) and collagen type Ⅰ (COL-Ⅰ) in kidney tissues. Western blotting was further performed to measure the expression levels of SLC7A5 and transforming growth factor-β1 (TGF-β1), as well as the phosphorylation levels of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway-related molecules. Real-time quantitative PCR was used to verify changes in the mRNA levels of SLC7A5, α-SMA, and COL-Ⅰ in kidney tissues. Results Compared with the control group, the experimental group showed reduced destruction of renal tissue structure and a significantly lower pathological injury score (P<0.05). Additionally, collagen deposition in the extracellular matrix was decreased, and the percentage of collagen fiber area was significantly reduced (P<0.001) in the experimental group. The levels of fibroblast activation markers α-SMA and COL-Ⅰ were significantly lower in the experimental group (both P<0.001). The expression levels of SLC7A5 and TGF-β1 were also significantly decreased (P<0.001), and the phosphorylation levels of mTORC1 signaling pathway-related proteins 4E-BP1 and mTORC1 were significantly reduced (P<0.001). Real-time quantitative PCR confirmed that the mRNA levels of SLC7A5, α- SMA, and COL-Ⅰ in kidney tissues were significantly lower in the experimental group (P<0.001). Conclusion JPH203 may inhibit the progression of renal fibrosis in mice by suppressing SLC7A5 expression, regulating the mTORC1 signaling pathway, and altering fibroblast activation status.

Key words: Solute carrier family 7 member 5 inhibitor, JPH203, Mammalian target of rapamycin complex 1, Renal fibrosis, Unilateral ureteral obstruction model, Mice

CLC Number:

CUI Changwan,LU Yiping,YU Miao,et al. Inhibitory Effect of Solute Carrier Family 7 Member 5 Inhibitor JPH203 on Renal Fibrosis Induced by Unilateral Ureteral Obstruction in Mice[J]. Laboratory Animal and Comparative Medicine, 2026, 46(2): 205-211. DOI: 10.12300/j.issn.1674-5817.2025.092.

Figures/Tables 3

References 16

[1]	LI L, FU H Y, LIU Y H. The fibrogenic niche in kidney fibrosis: components and mechanisms[J]. Nat Rev Nephrol, 2022, 18(9):545-557. DOI:10.1038/s41581-022-00590-z .
[2]	KANAI Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics[J]. Pharmacol Ther, 2022, 230:107964. DOI:10.1016/j.pharmthera. 2021.107964 .
[3]	HUANG H R, ZHENG S M, WU J N, et al. Opsonization inveigles macrophages engulfing carrier-free bilirubin/JPH203 nanoparticles to suppress inflammation for osteoarthritis therapy[J]. Adv Sci, 2024, 11(22):1-20. DOI:10. 1002/advs.202400713 .
[4]	SAITO S, ANDO K, SAKAMOTO S, et al. The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism[J]. Cancer Sci, 2024, 115(7):2461-2472. DOI:10.1111/cas.16191 .
[5]	WU T G, YU Z Z, DAI J H, et al. JPH203 alleviates peritoneal fibrosis via inhibition of amino acid-mediated mTORC1 signaling[J]. Biochem Biophys Res Commun, 2024, 734:150656. DOI:10.1016/j.bbrc.2024.150656 .
[6]	SZWED A, KIM E, JACINTO E. Regulation and metabolic functions of mTORC1 and mTORC2[J]. Physiol Rev, 2021, 101(3):1371-1426. DOI:10.1152/physrev.00026.2020 .
[7]	WU R Y, LI J W, TU G W, et al. Comprehensive molecular and cellular characterization of acute kidney injury progression to renal fibrosis[J]. Front Immunol, 2021, 12:1-8. DOI:10.3389/fimmu.2021.699192 .
[8]	GYIMESI G, HEDIGER M A. Transporter-mediated drug delivery[J]. Molecules, 2023, 28(3):1-52. DOI:10.3390/molecules28031151 .
[9]	BAO L Y, FU L Z, SU Y J, et al. Amino acid transporter SLC7A5 regulates cell proliferation and secretary cell differentiation and distribution in the mouse intestine[J]. Int J Biol Sci, 2024, 20(6):2187-2201. DOI:10.7150/ijbs.94297 .
[10]	LEE Y C, JIN C H, OHGAKI R, et al. Structural basis of anticancer drug recognition and amino acid transport by LAT1[J]. Nat Commun, 2025, 16(1):1-12. DOI:10.1038/s41467-025-56903-w .
[11]	HAYASHI K, SAEKI M, MIURA K, et al. JPH203, a LAT1 inhibitor, alleviates steroid-resistant murine airway inflammation mediated by Th17 cells[J]. Allergy, 2023, 78(10):2780-2783. DOI:10.1111/all.15798 .
[12]	HÄFLIGER P, GRAFF J, RUBIN M, et al. The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model[J]. J Exp Clin Cancer Res, 2018, 37(1):234. DOI:10.1186/s13046-018-0907-z .
[13]	KAHLHOFER J, TEIS D. The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: Physiological and patho-physiological implications[J]. Basic Clin Pharmacol Toxicol, 2023, 133(5):459-472. DOI:10.1111/bcpt.13821 .
[14]	MARKOWICZ-PIASECKA M, HUTTUNEN J, MONTASER A, et al. Hemocompatible LAT1-inhibitor can induce apoptosis in cancer cells without affecting brain amino acid homeostasis[J]. Apoptosis, 2020, 25(5-6):426-440. DOI:10.1007/s10495-020-01603-7 .
[15]	KIM Y A, GU H, GWON M G, et al. Synthetic non-coding RNA for suppressing mTOR translation to prevent renal fibrosis related to autophagy in UUO mouse model[J]. Int J Mol Sci, 2022, 23(19):1-13. DOI:10.3390/ijms231911365 .
[16]	PEI X L, ZHENG F X, LI Y, et al. Niclosamide ethanolamine salt alleviates idiopathic pulmonary fibrosis by modulating the PI3K-mTORC1 pathway[J]. Cells, 2022, 11(3):1-22. DOI:10.3390/cells11030346 .