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Cited by 46Kidney Stones and Urolithiasis TreatmentsPeroxisome Proliferator-Activated ReceptorsGout, Hyperuricemia, Uric Acid

Pioglitazone decreased renal calcium oxalate crystal formation by suppressing M1 macrophage polarization via the PPAR-γ-miR-23 axis

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Chen, Zhiqiang, Yuan, Peng, Sun, Xifeng, Tang, Kun, Liu, Haoran, Han, Shanfu, Ye, Tao, Liu, Xiao +7 more·2019·American Journal of Physiology-Renal Physiology
DOI 10.1152/ajprenal.00047.2019
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Abstract

Interaction of pioglitazone (PGZ) and macrophages (Mps) in renal crystal formation remains unclear. In the present study, we investigated the possible mechanisms involved with Mps of PGZ in suppressing renal crystal formation. Crystal formation in the mouse kidney was detected using polarized light optical microscopy and Pizzolato staining. Gene expression was detected by Western blot analysis, quantitative RT-PCR, immunohistochemistry, immunofluorescence, and ELISA. Mp phenotypes were identified by flow cytometric analysis. Cell apoptosis was detected with TUNEL assay, and tubular injury was detected with periodic acid-Schiff staining. Interaction of peroxisome proliferator-activated receptor (PPAR)-γ and promoter was determined by chromatin immunoprecipitation assay. Luciferase reporter assay was performed to authenticate target genes of miRNA-23 (miR-23). Recombinant adenovirus was used to elucidate the role of miR-23 in vivo. Renal crystal formation, inflammation, tubular injury, and cell apoptosis were significantly marked in glyoxylic acid-treated groups and significantly decreased in PGZ-treated groups. PGZ significantly reduced Mp infiltration and M1 Mp polarization in the kidney. In vitro, PGZ shifted crystal-stimulated M1-predominant Mps to M2-predominant Mps, which were anti-inflammatory. PPAR-γ could directly bind to one PPAR-γ regulatory element in the promoter of pre-miR-23 to promote expression of miR-23 in Mps. We identified two downstream target genes of miR-23, interferon regulatory factor 1 and Pknox1. Moreover, miR-23 decreased crystal deposition, M1 Mp polarization, and injury in the kidney. This study has proven that PGZ decreased renal calcium oxalate crystal formation and renal inflammatory injury by suppressing M1 Mp polarization through a PPAR-γ-miR-23-interferon regulatory factor 1/Pknox1 axis. PGZ is liable to be a potential therapeutic medicine for treating urolithiasis.

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  • Pioglitazone modulates macrophage polarization by targeting IRF1 and Pknox1 through miR-23, transforming inflammatory M1 macrophages into anti-inflammatory M2 macrophages, reducing renal macrophage infiltration, and decreasing calcium oxalate crystal formation and renal inflammatory damage.

    “Pioglitazone modulates macrophage polarization by targeting interferon regulatory factor 1 (IRF1) and Pknox1 through miR-23, transforming inflammatory M1 type macrophages into anti-inflammatory M2 type macrophages, significantly reducing renal macrophage infiltration, thus decreasing calcium oxalate crystal formation and renal inflammatory damage [28].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [28]

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Authors
Chen, Z., Yuan, P., Sun, X., Tang, K., Liu, H., Han, S., Ye, T., Liu, X., Yang, X., Zeng, J., Yan, L., Xing, J., Xiao, K., Ye, Z., & Xu, H.
Affiliations
  • Tongji Hospital (CN)
  • Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • First Affiliated Hospital of Xiamen University (CN)
  • ShenZhen People’s Hospital (CN)
Corresponding author
Xu, Hua
ORCID
Venue
American Journal of Physiology-Renal Physiology
Publisher
American Physiological Society
Published
2019-07-01
Volume
317
Issue
1
Pages
F137-F151
ISSN
  • 1522-1466 (ISSN-L)
  • 1931-857X
DOI
10.1152/ajprenal.00047.2019
OpenAlex
W2945537055
Cited by
46
References
55
Citations by year
2026: 3 · 2025: 4 · 2024: 12 · 2023: 4 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 2
FWCI
4.23
Type
journal article
Language
en
Update notices
correction (2022-03-15)
Open access
Locations
  • American Journal of Physiology-Renal Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (NSFC) (81470935)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Kidney Stones and Urolithiasis Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
Keywords
pioglitazone, M1 macrophage polarization, PPARγ, miR-23, IRF1, urolithiasis, renal inflammation, renal tubular injury, macrophage infiltration, anti-inflammatory therapy
MeSH terms
Pioglitazone, Animals, Anti-Inflammatory Agents, Binding Sites, Calcium Oxalate, Crystallization, Disease Models, Animal, Gene Expression Regulation, Hyperoxaluria, Kidney, Macrophages, Male, Mice, Inbred C57BL, Phenotype, Promoter Regions, Genetic, Signal Transduction, Apoptosis, Homeodomain Proteins, MicroRNAs, PPAR gamma, Interferon Regulatory Factor-1, Urolithiasis

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