Academic Journal
Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.
| Τίτλος: | Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis. |
|---|---|
| Συγγραφείς: | Li P; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Urology, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China., Ma Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Li Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Jian Z; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Yang M; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Fu Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Yang D; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yangdx@scu.edu.cn., Wang K; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: wangkj@scu.edu.cn., Zhao M; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: eyoung0801@163.com. |
| Πηγή: | Redox biology [Redox Biol] 2026 Sep; Vol. 95, pp. 104292. Date of Electronic Publication: 2026 Jul 07. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| Ιατρικοί όροι (MeSH): | Calcium Oxalate*/metabolism , Calcium Oxalate*/chemistry , Kidney Tubules*/metabolism , Kidney Tubules*/pathology , Phenylalanine*/metabolism , Phenylalanine*/blood , Nephrolithiasis*/metabolism , Nephrolithiasis*/pathology , PPAR delta*/metabolism , Fatty Acids*/metabolism, Animals ; Humans ; Mice ; Oxidation-Reduction ; Cell Line ; Glyoxylates ; Male |
| Περίληψη: | Calcium oxalate (CaOx) nephrolithiasis is usually framed as a physicochemical disorder of urinary supersaturation, yet stable crystal retention also requires a permissive tubular epithelial state. Here, we tested whether circulating phenylalanine (Phe) functions as a systemic priming factor that sensitizes renal tubular epithelium to CaOx crystal retention under lithogenic stress. Targeted amino-acid metabolomics in patients with CaOx stones, two-sample Mendelian randomization, glyoxylate-induced mouse nephrolithiasis, HK-2 cell injury assays, renal transcriptomics, pathway-rescue experiments and a Corydalis yanhusuo polysaccharide (CYPN-1) intervention were integrated in a staged translational design. Plasma Phe was elevated in CaOx stone formers, and genetically predicted Phe was positively associated with kidney stone risk without evidence of reverse causality. Phe loading did not independently generate stones but markedly amplified glyoxylate-induced renal crystal deposition and oxalate-triggered crystal adhesion to tubular epithelial cells. Mechanistically, Phe suppressed a PPARδ-CPT1A fatty acid oxidation program, increased reactive oxygen species and lipid peroxidation, and induced a redox-lipotoxic tubular phenotype. Activation of PPARδ or CPT1A rescued fatty acid oxidation signaling, lowered oxidative injury and reduced crystal burden in vitro and in vivo. CYPN-1 lowered circulating Phe, reshaped Phe-related gut microbial functions, restored tubular PPARδ-CPT1A signaling and attenuated crystal deposition. These data identify Phe as a modifiable metabolic sensitizer of tubular redox vulnerability under lithogenic stress and support CaOx nephrolithiasis as a disease in which luminal crystallization and circulation-facing metabolic injury converge at the renal tubule. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| References: | Nat Rev Nephrol. 2021 Jun;17(6):417-433. (PMID: 33514941) Mol Neurobiol. 2021 Jun;58(6):2897-2909. (PMID: 33550493) Mil Med Res. 2024 Sep 18;11(1):64. (PMID: 39294748) Biomater Sci. 2025 Mar 11;13(6):1512-1528. (PMID: 39928054) Int J Biol Macromol. 2024 Jun;271(Pt 2):131982. (PMID: 38724335) Front Immunol. 2023 May 09;14:1142207. (PMID: 37228601) Genet Epidemiol. 2013 Nov;37(7):658-65. (PMID: 24114802) Free Radic Biol Med. 2002 May 1;32(9):906-11. (PMID: 11978492) Phytomedicine. 2024 Nov;134:156027. (PMID: 39270592) Genet Epidemiol. 2016 May;40(4):304-14. (PMID: 27061298) Adv Sci (Weinh). 2025 Mar;12(10):e2403992. (PMID: 39836526) Phys Chem Chem Phys. 2021 Dec 15;23(48):27294-27303. (PMID: 34850794) Cell Death Dis. 2025 Jul 31;16(1):579. (PMID: 40744915) J Clin Med. 2017 Jul 19;6(7):. (PMID: 28753922) Front Pharmacol. 2022 Apr 20;13:805281. (PMID: 35517820) BMJ. 2018 Jul 12;362:k601. (PMID: 30002074) Mol Genet Metab. 2018 Nov;125(3):228-234. (PMID: 30266197) Cell Metab. 2020 Aug 4;32(2):154-175. (PMID: 32649859) Redox Biol. 2023 Dec;68:102957. (PMID: 37977043) Nat Rev Nephrol. 2024 Dec;20(12):771-788. (PMID: 39198707) Mol Genet Metab Rep. 2024 Apr 23;39:101084. (PMID: 38694233) Redox Biol. 2023 Sep;65:102826. (PMID: 37516014) Metabolism. 2021 Jan;114:154338. (PMID: 32791172) Int J Epidemiol. 2019 Jun 1;48(3):728-742. (PMID: 30561657) Urolithiasis. 2017 Apr;45(2):177-183. (PMID: 27228999) BJU Int. 2017 Jul;120(1):109-116. (PMID: 28236332) Microbiome. 2024 Sep 17;12(1):175. (PMID: 39289694) Mol Genet Metab. 2022 Jun;136(2):111-117. (PMID: 35379539) Int J Epidemiol. 2017 Dec 1;46(6):1985-1998. (PMID: 29040600) Arch Biochem Biophys. 2024 Nov;761:110187. (PMID: 39490615) Elife. 2018 May 30;7:. (PMID: 29846171) Nature. 2017 Nov 30;551(7682):648-652. (PMID: 29168502) PLoS One. 2024 Sep 26;19(9):e0310947. (PMID: 39325731) Lipids Health Dis. 2024 Feb 3;23(1):37. (PMID: 38308271) Am J Kidney Dis. 2023 Nov;82(5):617-634. (PMID: 37565942) BJU Int. 2020 Apr;125(4):586-594. (PMID: 31916369) Biomed Pharmacother. 2023 Nov;167:115511. (PMID: 37729733) Free Radic Biol Med. 2023 Oct;207:120-132. (PMID: 37451369) Front Immunol. 2023 Jun 12;14:1114129. (PMID: 37377971) Urolithiasis. 2020 Feb;48(1):27-35. (PMID: 30949730) Free Radic Biol Med. 2011 Jan 15;50(2):345-53. (PMID: 21047550) Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253) Nat Rev Urol. 2022 Dec;19(12):695-707. (PMID: 36127409) Nat Genet. 2018 May;50(5):693-698. (PMID: 29686387) Nat Commun. 2019 Nov 15;10(1):5175. (PMID: 31729369) Nature. 2023 Jan;613(7944):508-518. (PMID: 36653562) Mol Biol Rep. 2024 Feb 20;51(1):314. (PMID: 38376557) Redox Biol. 2023 May;61:102648. (PMID: 36871182) Nat Rev Nephrol. 2024 Feb;20(2):101-119. (PMID: 37857763) J Transl Med. 2024 Jan 2;22(1):9. (PMID: 38169402) Carbohydr Polym. 2022 Jul 1;287:119355. (PMID: 35422305) Clin Kidney J. 2025 Aug 04;18(9):sfaf244. (PMID: 40978115) Life Sci. 2021 Jan 15;265:118853. (PMID: 33278384) Mol Med Rep. 2022 Aug;26(2):. (PMID: 35703358) Eur Urol. 2012 Jul;62(1):160-5. (PMID: 22498635) Signal Transduct Target Ther. 2023 Jan 21;8(1):41. (PMID: 36681678) Mol Cell Endocrinol. 2024 Mar 1;582:112139. (PMID: 38128823) J Anim Sci Biotechnol. 2022 Jan 22;13(1):18. (PMID: 35074004) Heliyon. 2023 Oct 29;9(11):e21431. (PMID: 38027795) Genet Med. 2025 Jan;27(1):101289. (PMID: 39630157) Nat Metab. 2025 Apr;7(4):808-822. (PMID: 40087408) J Sep Sci. 2023 Dec;46(24):e2300452. (PMID: 37880903) Aging Dis. 2015 Oct 01;6(5):390-9. (PMID: 26425393) J Am Soc Nephrol. 2005 Aug;16(8):2395-402. (PMID: 15944338) Redox Biol. 2024 Jun;72:103140. (PMID: 38593629) Curr Opin Urol. 2023 Mar 1;33(2):84-89. (PMID: 36210763) Eur Urol. 2024 Oct;86(4):343-363. (PMID: 39069389) Neurobiol Dis. 2008 Dec;32(3):385-90. (PMID: 18755275) Orphanet J Rare Dis. 2017 Oct 12;12(1):162. (PMID: 29025426) Urolithiasis. 2021 Feb;49(1):27-39. (PMID: 32870387) Adv Nutr. 2023 May;14(3):555-569. (PMID: 36906146) PLoS Med. 2015 Mar 31;12(3):e1001779. (PMID: 25826379) Mol Genet Metab. 2025 Jun;145(2):109125. (PMID: 40378670) Nat Genet. 2021 Jan;53(1):54-64. (PMID: 33414548) Nat Rev Dis Primers. 2016 Feb 25;2:16008. (PMID: 27188687) J Endourol. 2016 Mar;30(3):246-53. (PMID: 26576717) Redox Biol. 2024 Nov;77:103373. (PMID: 39357422) Microbiol Res. 2024 May;282:127663. (PMID: 38422861) Nucleic Acids Res. 2025 Oct 28;53(20):. (PMID: 41189055) Lancet. 2010 Oct 23;376(9750):1417-27. (PMID: 20971365) Lancet. 2012 Mar 31;379(9822):1173-4. (PMID: 22463865) Molecules. 2021 Dec 10;26(24):. (PMID: 34946576) |
| Contributed Indexing: | Keywords: Calcium oxalate; Gut microbiota; PPARδ; Phenylalanine; Redox lipotoxicity; Renal tubule |
| Substance Nomenclature: | 2612HC57YE (Calcium Oxalate) 47E5O17Y3R (Phenylalanine) 0 (PPAR delta) 0 (Fatty Acids) 0 (Glyoxylates) JQ39C92HH6 (glyoxylic acid) |
| SCR Disease Name: | Nephrolithiasis, Calcium Oxalate |
| Entry Date(s): | Date Created: 20260710 Date Completed: 20260729 Latest Revision: 20260813 |
| Update Code: | 20260814 |
| PubMed Central ID: | PMC13377012 |
| DOI: | 10.1016/j.redox.2026.104292 |
| PMID: | 42431158 |
| Βάση Δεδομένων: | MEDLINE |
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